HUE029440T2 - Oral medicament for the modified release of at least one active principle, in multimicrocapsule form - Google Patents

Description

Oral iiiM product wifi modified reless« of ot tel one active principle m lorm ÄM·

The field of the inveatfonts ih||Mmedkinft pdiipls ör more particularly of the type comprising one m more active p^oelpiea The aim of the invention is to provide an improved oral medicinal product that east be administered in one or more daily doses, with modified release of active principle (in particular one active principle}, whereby the prophylactic and therapeutic efficacy of said medicinal product is Improved, This aim is achieved by f the mnitimkrocapsular oral pharmaceutical form according to the invention in which the active principle release π controlled bx a dual release trigger mechanism; “time-dependent trigger“ and “pH-dependsat trigger". Said medicinal product comprises micmcapsules with modified release of active principle, each containing a core comprising the active principle and one or more swelling agents, and at least one coating tor the modified release of the active principle. FIELD OF THE ItWENfÍOÍ

The field of the pmm% invention k that of mioropameulale ^ptete with delayed anti controlled telesse of activa pnnelpiefs) AF(s). intended for oral adnuntstmhoo.

The APs envisaged In the present Invention aye in particular those which have an absorption essentially limited to the upper parts of the g&strohdestlnal tract, located upstream of the colon (of the ileocecal junction), and which represent a large majo&fy of pharmaceutical active principles. The active., .principles, more specially targeted are active principles with "low solubility".

More specifically, the invention relates to a mieropartienlate pharmaceutical term wilt delayed and controlled release tor which the controlled release phase Is triggered in a definite manner by means of a double mechanism: "time-dependent" release triggered after a certain residence firne In the stomach, and "pHMependent" release triggered by a change in pH when the particles enter the small intestine and which begins without any lag time. The microparticles of the present Invention arc microcapsaies containing at least one active principle (AF.g with the exclusion of earvedikd, of mean padlóié sise of less than 2IM) microns, individually coated with a eoalina hint for the delayed and controlled release of Été AF.

The invention also relates, is the mieroeapsules with modified release pf at least one active principle, taken as such in the present disclosure, the expression "actAc principle nith low solubility" deuetosany active principle, with the exclusion of carvedilol, which has a solubility of less than or equal to approximately 50 g/L preferably less than or equal to approximately 20 g/L even more preferably less than or equal to approximately 5 g/1 and, for example, less than or equal to;

0.1 g/L

In the present disclosure, the term “mieroeapsules" denotes microparticles of active principle coated with at least one coating for the modified release of at least one active principle (in particular an active principle with low solubility).

In the present enclosure, the terot "carvedilol" denotes carvedilol per re, one or more pharmaceutically acceptable salts of carvediloh or one or more pharmaceutically acceptable esters of carvedilol or any mixture of these active agents.

In tie: present disclosure, the expression "modified release" denotes, without distinction, a prolonged release of the active princtplc(s), beginning as soon as the rmorooapsules are brought Into contact with the dissolving medium and extending from 0,5 h to 24 h, preferably from I; to IÖ h, or a release of the active pTÍneipie(s) that begin® only after a predetermined period of time (lag; time) ranging, ihr example, from. 0,5 to several hours, with a time to release |0% of the active principle(s) which is typically several hours and which can extend isâl to 30: hours, lor example,

In the present diselosure, the expression “immediate release’' denotes a release of the active prineiple(s) that begins as soon as the pharmaceutical form is brought into contact with the dissolving medium (in vivo or in vitro) with a time to release 80% of the. active prlnclple(s) which is less than dr eqttal to I h and, for example, less than or equal to 20 min.

Systems with delayed and controlled release of active principie(sj are particularly useful when it is desirable, for chronohlologieal reasons, for the active principle(s) to be "hioabsorbed" at a specific time of the day in order to he in phase with the circadian cycle. It may, for example, be advantageous for the active principle^} to he bkmhsorbed very early in the morning in order to ensure therapeutic cover when the patient wakes up, without, however forcing him or her to wake op early- To do this, the pharmaceutical system Ingested by the patient, for example in the evening aller the meal, shoud allow a delayed release of the active prineiplets).

Given that another rule required to the specialist in galenics is to guarantee that the prescribed medicinal product will be absorbed by the patient, it is essential, in the case of a delayed release form, to have a complete guarantee of release of the active principle at a given time so as to obtain the therapeutic effect. Now, u must be noted that the delay cd-re lease terms thai existed up until recently could not definitely ensure release of the AP within a stipulated time period, which can be vital for the patient In certain pathologies, such as, for example, that of cardiovascular diseases,

Another targeted property .tor systems with delayed and controlled release of active prlnciplefs) is to improve the plasma concentration profile obtained after administration, The intended aim is to obtain a plasma proliié which is maintained above the effective tlpmpuie concentration for as long, as possible in order to maximize the duration of action of the active principle(s), and therefore its (their) therapeutic efficacy. This aim ebmes ip against the residence time of the active principles) in the blood compartment, which is roost commonly much less than one day. To achieve this aim, It would therefore be advisable to prolong the emuhsmpiton a ne of rv ,etive prineiple(s). AP(s), by a judicious adjustment of the release of the active ynncipGtm m hunt of its (then) bmubsorptioo window, in the upper putts of tire gastrointestinal tract.

Various forms with modified release of active principlels} lave been developed, in order to attempt to solve the abovemendoned problems ofehronotherapy and ofmaintenance of a high plasma profile for as long as possible. pH'"dependent delayed-reiease forms which are obtained by coating the active principlets) by means of an enteric polymer layer, tor example a layer of methaeryUc acid and methacrylic acid methyl ester copolymer EUDRAGIT™ L, are thus known. This type of enteric coating is known to provide a reduced permeability In the acidic pH conditions of the stomach and to dissolve when the pH goes up to,', i. .due close v that which occurs m the am )! intestine, thus releasing the active principlets). However, the Intra» and biter-individual variability in the gastric pH conditions and in the gastric emptying time do not make it. possible to definitely ensure release of the active principle(s) aber a given period of time.

Delayed release systems that are only dependent on the time after ingestion ("time» dependent'*}- t,e. systems for which the release of the active prindple(s) is triggernd alter a given period of time in the gastrointestinal tract, are, further, known and are not satisfactory either. Indeed, due to the intim and inter-individual variability in gastric residence time, the release of the active prinoiple(s) can occur aller said active principles) has(have) passed in Iront ofits(their) absorption window, which is located, for most active principles, in the upper parts of the gastrointestinal tract. The bioabsorptiou can thus fee very poor or even aero.

How et er, it was not until the nviittmù ropattreulsi& pharmaceutical system as disclosed in PCT patent application W0-A-O3/O3Ô878 to obtain very significant progress, in particular with regard to the abovenamtkmed problems of chronotherapy and of mainte stance cd' a high plasma profile Cor as long as possible, 1'bis system with delayed, controlled and guaranteed release of the active principle; s) is characterised by a dead mechanism ibr triggering the release of the active principled): "time^ependeat* release triggered after a controlled time period in the stomach, without any change in pH, and "pll-dependcnH release triggered by a rise in pH when the pharmaceutical form enters the intestine. These two triggering factors for the release of the active prindpie(s) arc in series and confer very sate use to the pharmaceutical system. The release of the active principle^} is thus guaranteed alter a preset lag time, even if the variation in pH has not occurred as triggering means, i.e. even If the pharmaceutical form has not moved from the stomach into the intestine. These miccocapsulcs with a diameter between 200 and 601) microns are characterised by a coating film based on a hydrophilic polymer A of the EUDRAGÍF M L type combined with a hydrophobic compound B, such as a vegetable wax (LUBRITAB™) with a melting temperature between 40 and 90,degree. €„ the B/A ratio ~ 0,2-1,5, These mtcrocapsules have an in vitro dissolving behavior such that, at constant pi-1 1.4, a lag phase between 1 and 5 hours is observed, followed by an active principle release phase, and such that the change from pH 1A to pH 4B results in active principle release without any in vine lag time.

The muitimi cropartic ο I at e pharmaceutical system according to PCX patent application WO-Ä-03/030878 also makes It possible to adjust the lag time preceding the release of the AP in the stomach by taking into consideration the physiological conditions of the gastrointestinal tract in humans. This advantageous method is thus a means for minimising the interindivsdual variability of absorption of the AP. Indeed, according to the well brown results of Davis et al, J. of ComroUnd Mease, 3, 27-38 (1985), the residence tune of a preparation in the stomach Is very variables in the order of 0,5 to ;l# hours, Now, specifically, the abovemetdteed system makes It possible to release the active principle in. the stomach after a given constant lag time within this range 0.540 hoirs, such that, from one individual ip another, or even from one day to another for the same· Individual, the action time of the medicinal product is the same.

In lact, the mlcroparticuiate oral pharmaceutical form with delayed and controlled release of All, according to W0-A-Ö3/O3878, has simultaneously the following properties: * the release of the AP can be triggered by two ways; o by Nime-dependenr release when the residence time of the particles ht stomach exceeds a period of 5 hours; 5 by “pH-dependent'" release, which begins without any lag time when the system enters the intestine and the pH increases. These two AP release triggering factors that are in series ensure Ute release of AP after a preset lag time, even if the variation in pH has not occurred as a triggering means: *: it consists of a plurality of small mnnoeapstdes of coated AP; * the mass fiactiou of coating excipients is United, ft should be noted that the problem of maintaining a high plasma profile for as long as posihle: can be solved, in accordance with the invention according to WQ-A-03/03878, by using a mixture of nneroeapsnles with different delayed and controlled release profiles, Htis provides release profiles exhibiting several waves of release or ensuring, by means of an appropriate regulation of the various tractions, a constant level of plasma concentration or the ae 11%¾ pr i ne i p ie{ s k

TECHNICAL PROBLEM

Nevertheless this micropm-tleuiate oral pharmiteetÉ'cat &*' with delayed and controlled release of active prineiplets), according to further improved,

In fact, it Is known that, to be released, a microencapsulated active principle must first of all be reached by the fluids of tbc gastrointestinal tram which, to do this, have to go through the coating film of the microcapsulcs, The microencapsulated active principle: can then dissolve in fhpe Ëuids. The active principle solution thus obtained can subsequently diffuse out through lie coaling iiim(s) of the microcapsnl.es. Hies, to obtain a lag rime between 0,5 and 7 h, for example of 2-3 k it is important for the coating film of the microcapsulcs to have a sufficient thickness (in pm) and/or to represent a sufficient coating degree DC (as % by weight), so that the entry time of a liquid such as water or a gastrointestinal tract fluid into the microcapsuk allows delayed release of the active principle. This minimum thickness may, for example, correspond to a DC of 10-40%, for example,

Iqwever, when the. thickness of the film-coating is sufficient to result in a lag time, ft has been noted that, iu the case of active principles with low solubility, the hime-dependenf’ release and the "pTI-dependent" release of the active principle are still effective, but become slower, which can harm the bioavallahifky. For example, at least 80% by weight of the active principle is not released alter, for example, 16 b at pH::::?,0. in an in vitro dissolution test carried out according to the indications of the European Pharmacopoeia, 4th. edition, entitled' “Dissolution test for solid oral forms“: type II dissolutest in SINK conditions, maintained at degree C. and Mined at 100 rpm.

Therefore there exists, to date, a need for a pharmaceutical composition or multunierocapsidar oral medicinal product, with modified release of aetnc rnmapUqs :, mat Ls of the type oftho.se disclosed in WO-A~03'0311878 and that improves the latter, in particular to obtain, 1er active principles with low solubility, release of the active principle according to a dual "thne-dtrpendent” and "pH-dependent" triggering mechanism, with faster release Urnes to optimise the bioabsorption of the active prineipkm), oh,never the triggering mechanism for this release.

OBJEC1TVES

Due of the essential objectives of the invention is to provide an oral medicinal product that is improved compared to that described In WO-A-03/Ö3878. specifically a multi microcapsuk oral medicinal product with modified release of active prineipletsT in particular of active principles) with low solubility, which guarantees correct functioning of the dual "time-dependent" and “pILdeoendenf* triggering mechanism of the active principle release, ht particular-fhractive principles with low solubility.

Another essential objective of the invention Is to provide a multi microcapsule oral medicinal product with modified release of active principle*$), that makes it possible to judiciously adjust the release kinetics of the active principle all along its absorption window in the gastrointestinal tract, so that the plasma eonceniration proliié N mainlined chose the effective therapeutic concentration for as long as possible, and in particular for a time period greater than that of the immediate-release form. pother essential objective of the invention is to provide a multöniÉío^pule má medicinal poduet with modified release ot'active ptineipleis), which provides a solution suitable for tie :Ü>hle#of chrcmoiberepy and.for ôte -difficulties of compliance relating thereto.

Another essential objective of the invention is to provide a muitmueroeapsnle oral médicinal product with modified release of active prmciple(s), which makes it possible to readily eombhp at least Pvo active principles hi the same pharmaceutical form.

Another essential objective of the Invention is to provide a multimicrocapsuSc oral medicinal product with modified release of active principle!s}, which, contrary to the compact monolithic forms* provides a decreased interindlvidna! variability.

Another essential objective of the invention is to provide a mnltimicmeapsnle oral medicinal product with modified release of active principles), which allows an increase of the gastrointestinal transit time and of absorption of the active principle in the upper parts of the gastrointestinal tract,

Another essential objective..of the invention is to provide a mnhimicrocapsule oral medicinal product with modified release of active prineipie(s), said medicinal product existing in a presentation form that can be administered once a day, which would, represent a significant progress, in particular in terms of patient compliance:.

Another essential objective of the invention is to provide a multinricroeapsule oral medicinal product with modified release of active princip!e(s), which may 1m prpdieed according to a robust industrial process.

Another essential objective of the invention is to provide a multimicrocapsule oral medicinal product with moot tied 5 dense oi active principle! s\ which is easy to prepare, for example by depositing a coating by spraying onto microparticles containing active principle with low solubility.

Another essential objective of the in vention is to provide a mulUrnicroeapsule oral medicinal product with modified release oi active principled) and having high contents of active principled), for example up to 60% by weight of the rmcrocapsules.

Another essentia! objective of the invention is to provide an oral medicinal product with modified release of active prineiple(s), containing a plurality of microcapsules and having a dose-independent active principle in vino release profile.

Another essential objective of the invention is to provide a mukimicroeapsule oral medicinal product with modified release of active principle^), in which the microcapsules are non-enteric, Le. do not release the active principle only vs hen the pH goes from 1.4 to 7,0 (gastric pH ::s> intestinal pH).

Another essential objective oi the invention is to provide a roulthnicroeapsule oral medicinal product with modified release of active principled), which makes it possible to obtain a plasma concentration !C24h) of active principk(s) as high as possible, 24 h after administration per os.

Another essential objective of the invention is to provide mierocaptules with modified release of active principles which can he used in particule tor preparing a medicinal prodocl as defined by the specifications stated in the above objectives,

«RIBf DISCLOSURE OF THE INVENTION

These objectives, among others, are achieved by the invention which relates, firstly, to an oral medicinal product comprising a plurality of mierocapsules with modified release of active princlpk'(s), at least some of said mierocapsules individually consisting of a microparticle comprising at least one active principle »» in particular at least one active principle with low solubility (with the exclusion of earvesilol) coated with at least one coating for the-modified release of the active prmclple(s| said release being controlled by two distinct triggering mechanisms» one being based on a variation in pH and the other triggering the release of the active principie(s) after a predetermined residence time in the stomach, said coating also conferring on the mleroeapsnles an in vitro dissolution behavior such that: - at. constant pH 1.4, fee dissolution profile comprises a lag phase less than or equal to ? hours, preferably less than or equal to 5 hours, and even more preferably between l and 5 hours; • the change front pH 1.4 to pH 7,0 results in a release phasedhat begins without any lag time; this medicinal product being characterized in feat at least some of said mierocapsules comprise at least one- swelling agent, and in that the fraction by weight of the active prmmplopu released daring the lag phase is ÍÉI&ÍÜÍ&: oie^qafeto 15% by weight per hoax, preferably less than or equal to 10% by weight per bout; and; oven more: preferably less than or equal to $% by weight pet hour.

The In vitro dissolution behavior is determined according to the indications of the European Pharmacopoeia, 4th edition, entitled; ''Dissolution test for stchd oral forms"; type II dissoiutevt carried out under SINK conditions, maintained at 37.degree. C. and stirred at 100 rpm. lire medicinal product according to the invention overcomes fee abovemenridned technical problem, namely the release of active principle(s). AP(s), with low solubility according to a dual "time-dependent" and "pi 1 dependent'1 triggering mechanism, thereby accelerating the release of the active principle, in particular compared to the release times obtained by the Invention according to WO-A-03/Ö3878. In doing so, fee medicinal product according to the invention ultimately improves the prophylactic and therapeutic efficacy of such active principles with low solubility.

However, the medicinal product according to thé: invention Is also advantageous In that if provides in particular the following advantages: - possibility of an easy combined use of at least two active principte(s); reduced bate rimái vi dual variability; - increase of the gastrointestinal transit time and of the absorption of fee active principle in the upper prnta of the gastrointestinal tract; - proportionality between the dose and the pharmacokinetic profile; - ease of ingestion by the patient and possibility of administration, for example, once a day, which ensures that the compliance is observed and therefore guarantees efficacy; .« reproducibility of the release kinetics, from one industrial batch to another; industrial; development is therefore possible, without this harming the therapeutic performances of the encapsulated active principle^) «.for example nahe principle"* with low .solubfetU. ~ easy and economical preparation, tor example by depositing a eoatln§ by spraying onto microparticles containing active principle with low solubility; ~ possibility of having high contents of actroe principtefs)* tor example up to 60% by weight of the microeapsolest - plurality of mtsroeapsules having a dose-independent active principle in vitro release profile; - non-enteric microcapsuks, i.e, which do not release the active principle only when the pH goes from 1 -4 to 7.0 f gastric pR:::>intesdnal pH); * plasma concentration oí acme princtpkts) .ft h after a*iroinisf.raoun per os close to or greater than that which would be obtained with an immediate-release form taken in several dose.v

PpXAILED DISCLOSURE OF THE INVENTION in accordance with the invention* the swelling agent comprises at least one phannaeeutieally acceptable hydrophilic compound that exhibits a degree of swelling in water at 2S.degree. C, greater than or equal to 10% by weight» preferably greater than or equal to 15% by we|g|tC and even more preferably greater than or equal to 20%.

According to a tunable characteristic of the invention, the swelling agent ts chosen from those that allow the microcapsules to release at least 505¾ by weight, of the active principle after 16 It at pH~l A and alter a lag phase of less than or equal to 7 hours, preferably less than or equal to 5 hours* anu even mote preferably between I and 5 hours, in an in vitro dissolution test carried out according to the indications of the European Pharmacopoeia, 4th edition., entitled: "Dissolution Test for Solid Oral Forms": type It dissolûtes! carried out under SIKK conditions, maintained at 3?.degree. C> and stirred at 100 rpm.

In accordance with the Invention* It is possible to adjust the release rate of the active prlnciplets) írom the mterocapnles at pH-4,4 by judiciously seiectiif| the concentration (Cd) of swelling agent.

When; the swelling agent is in mieroparilcuMe form, the sixe (Sd) of the swelling agent parities is advantageously selected within the mean diameter ranges* in pm, of between 5 and 200 pm, and prefesthly between IS and $0 pm.

The concentration (Cd) of swelling agent is selected withlMle ibllppag ronges of 16 by weight relative to the total weight of the microcapsufes; - 3 < Cd < 40, » proicrahly 4 5; CM < 30, ~ and even more preferably 5 < Cd < 25.

According to a preferred embodiment of the invention, the swelling agent is chosen front the group of follow mg products; 0 crosslinked polyvinylpyrrolidones (e.g, poiyplasdone or crospovklone), 0 crosslinked carboxyalkylcelluloses: crosslinked catboxynieihykdloloses (e,g. crosslinked; sodium eroscarmellose), &amp;: and also hydrophilic polymers with high fpoiar weight (greater than or equal:: to 100 000 D), such as: • polyvinylpyrrolidones, * polyaiks kne oxides t>\g. polyethylene oxide or polypropylene oxide), * (hydroxyl aikyl)ceilulÉes (digy iydroxypropyl methylceilulose}, * carKíxyaikylcdlckvsos (e y ^arboxv meny 1er 11η1ο\οΝ '* celluloses (powder or mícrocrysialüne), * modified starches (for example modified w-ith sodium glyeolate), « natural starches (for example from com, wheat or potato), * sod.loots alginate, * polaerilin potassium, * and mixtures thereof.

Even «tore preferably, the swelling agent is chosen from the subgroup of following products“ o crossl inked polyvinylpyrrolidones (e.g. polyplasdnne or crospovidoneh and o ctosslinked carboxyalkyiceliuloses: crosslmked carboxymethylcclluloses (e.g. crosslmked sodium erascarmeliose).

To address the possibility that active principles (.for example with low solubility) would be poor!}· wetted by water and would therefore have a tendency to agglomerate, it Is proposed, according to an advantageous variant of the invention, that the medicinal product comprises at least one wetting agent, preferably chosen from the group of following products: o anionic surfactants, preferably in the subgroup of alkali metal or alkaline-earth metal..salts of fatty acids, stearic add and/or oleic acid being preferred, c· and/or nonionic surfactants, preferably in the following subgroup: » polyoxyethylenated oils., preferably pofyoxyethylenated hydrogenated castor oi, * poKovrednlcnO'pc'soxvp >,>p>lene <opol· cots, * poiyoxyethylenated sorbit an eaters, * polyoxyethylenated castor oil derivatives, * stearates, preferably calcium stearate, magnesium stearate, aluminum stearate or amp stearate, * stoary iiiumuates, preferably sodium stearylimtaratc, * glyceryl behenatey * and mixtures thereof

Advantageously, the medicinal product according to the invention comprises microcapsules of active princlple(s) that can release at least. 80% by weight of the active principled), after 12 h at pH™-?.?), in an in vitro dissolution test carried out according to the indications of the European Pharmacopoeia. 4th edition, entitled: "Dissolution fest for Solid Oral forms"; type 11 dissolute* carried out under SINK, conditions, tnaimain<^i M 3?.iegree. C> and stirred at 100 rpm.

The medicinal product according to the invention is mnltimiciocapsular, i.e. it comprises, inter alia, microcapsnles consisting of .microparticles of coated or film-coated active principle. These microparticles of active principle may, lor example, be microparticles of raw (pure) active principle in pulverulent form, matrix ψanales of active principle with various other ingredients, or alternatívok neutral mierospherex for example of cellulose or of sugar, coated with at least one layer comprising active principle

The modified release microcapanies of active principle can be compared to nucrounits containing at least one active principle and forming .4 leas* some of the constitutive elements of the medicinal product according to the invention.

Esch mlerocapsnle ea« cgoippae one or more active principles that are identical to or différent from one «.«other.

The medicinal product according to the invention can comprise microumts of active principle other thou micros.«pauka. They may he, for example, microparticles with immediate release of active pnneiple(s), 1 he latter may be, tor ex ant pic, uneoated -microparticles of active principle^* that, can be the same as those used ip the preparation of Ere mtcrceapsutes. according to the pvemiom

Each microparticle may comprise one of more active principles that are identical to or different from one another.

In addition, ail the mierounhs {microparticles and/or mierocapsui.es} constituting the medicinal product according to the invention may he made up of various populations of mierounhs, these populations differing from one another at least by vinne of the nature of the active principle(s) contained In these micro units and/or of the coating composition.

Regarding the structure of the mlcmcapsules used in the medicinal product according to the invention, two protonod embodiments of the miorocapstnes structure are given in detail hereinafter, without It being limiting.

According to a first embodiment, a least seme of the mtcrocapsules with modified release of active principiets) Individually comprise; c a microparticle of active principlets) coated with c- at least one coating for the modified release of the active prlncip|e{d}.

Preferably, the microparticle of active principled) is a granule comprising the aeiie principiets) surd one or mote pharmaceutically acceptable excipients.

Advantageously, the swelling aggpt(s) is (are) contained in the microparticle p|< grattule), R egard in g the wetting agenda), tt (they) is (are) preferably contained iu the microparticle te,g. granule) anchor in -the costing for modified release of the active principle^).

According to a second embodiment, at least some of the microcapsufes with modified of ease of act«, e pnnctplels) indh idnedh comprise' o a neutral core, o at least; one active layer comprising the active principiets) and costing the neutral core, and m mi least one coating for the modified release of the active principic(s).

According to a first possibility, the neutral core contains sucrose and/or dextrose and/or lactose.

According to a second possibility, the neutral core is a cellulose microsphere.

Advantageously, the neutral core has a mean diameter between 1 and 800 pnvaod preferably between 20 and 500 pm.

The active layer may optionally ^-moose, in uidmcm n> the active principiets;, one or more pharmaceutically acceptable excipients..

Advantageously, the swelling agentt» is (are) contained in the active layer. l*or example, this active layer comprises the active principle, at least one swelling a§®ot, at least one hinder and at least one surfactant.

Regarding the wetting agentfe), it (they) is (ate) preferably contained in the active layer,

Regarding now the coating composition of the microcapsufes with modified release of aetwe principle(sh the present Invention also consists tn selecting microcapsuies having the following speciftcitiest: o the coating for the modified release of the active principled) comprises a eontpshe material ® comprising: « at least one hydrophilic polymer A carrying poipssthat are lenlsfeÉiat neutral pH, » at least one hydrophobic compound 8; * representing a mass traction (weight % relative to the total weight ot the microeapsuies) < 40; and ο their mean diameter is less than 2000 pm, and preferably between H and fői ptttv ánd even more preferably between 100 and 600 urn.

According to another advantageous characteristic, the composite material AB for the coating for the modified release of the active principle with low solubility is such that: o the B/A weight ratio is between 0.2 and 1.5, preferably between 0,5 and 1.0, o and the hydrophobic compound B is selected from products that are crystalline m the solid state and have a melting point MpB > 40.deg.tee, ¢., preferably MpB > 50,degree, ¢., and even· more preferably 4§.de|ree. C,£ MpB > 90<degree, C.

According to a preferred embodiment, the hydrophilic polymer A is chosen iront: - A,a. copolymers of (meth)acrylk acid and (meth)acrylie acid alkyl esten and mixtures thereof; A.h. cellulose derivatises, preferably cellulose acetates, cellulose phthalates, cellulose succinates and mixtures thereof, and even more preferably hydroxypropyl methylcellulose phthalates, hydroxypropyl methylcellulose acetates, hydroxyprqeyi meth vice Italosé succinates and mixtures thereof; - and mixtures thereof,

The poly mem x that are et en more preferred are copolymers of (meth)acrylic acid and of (meth)aeryuc add alkyl (e,g. CI-C6 alkyl) esters. These copolymers are, for example, those commercialized by the company Rohm Pharma Polymers under the registered trade marks BU DR AGI Ï™, of series L and S (such as, for example. E l ID RA GIT*M 1.,100, S100, L30 D-55 and LI00-55). These copolymers are anionic enteric copolymers that arc soluble in aqueous medium at pt ls above those encountered in the stomach.

Still according to the preferred embodiment, the compound B is chose;· from the group of products below; ~ B,a, vegetable waxes taken on their own or as mixtures with one another; ~ B,b. hydrogenated vegetable oils taken on their own or «s mixtures with one another; * H.e> mono- and/or di- and/or triesters of glycerol and of at least one fatty acid; - B.d, mixtures of monoesters, diesters and triesters of glycerol with at least one tatty acid; - B.e. and mixtures thereof.

Even more preferably, the compound 8 is chosen from the group of the following products: hydrogenated cottonseed oil. hydrogenated soybean seed oil, hydrogenated palm oil, glyceryl behen&amp;te, hydrogenated castor oil, tristearin, trlpaltnitin, trixnynstin, yellow ws, tetei fat or fat that is useful as suppository bases, anhydrous dairy fats, lanolin, glyceryl paimhostearate, ,o\,e,d stew oe, laurvl maerogoiglycerides, cetyl alcohol, polyglyecryl dnsosteafate, diethykne glycol monostearate, ethylene glycol roonosteurate, omega 3 and any mixture thereof, preferably trove the subgroup of following products: hydrogenated cottonseed od, hydrogenated soybean seed oil, hydrogenated palm oil go eery beheo<ue, hydrogenated castor oil, tristearin, fripsirnitin, trimviistin and any mixité thereof.

In practice, and without if being limiting, compound 8 is preferably selected: o írom the group of products sold under the following trademarks: Pynasafofo C.utm#% Hydmbaxe™, DabrM. Castorwax™ €roduret*% f'ompritoB'f bterotevrM> Labritah™, Apt ill™, Akoime™, 9otfosurriM, llvdrocote™. Livopol™, Super Haitokn™, IMOLA™, iptona™, Protalan™, Akosoft™, Aknaol™. Cremao™, Msssupol™, Novata™, Suppodre™. Weeobee™. Witepsol™. Lauo!i#M, hveromega™, Estaram™,. SuppowemGA Gelucne'fo Free no! *% LrauWufofo Plurm fowosunqne?v. Gebot™. Hydrine™ and Monthyie™, and mixtures thereof; 0 and also Írom the group of additives for which, the codes are as follows! Ê ill, B Wl, i 903 and mixtures thereof; 1 and, preferably, trout the group of products sold ander the following foademarks: Dvnasan™ F6(>, Dynasan™ 114, Dynasan™ Uh, Dynasan™ 118, Cuitta™ IÄ, Hydrobase™ 6b-6fo Dub™ HFH, Compritçl™ SSS, Sterotex™ NF, Stmmm E, Lubritah™ and mixtures thereof

According to another advantageous characteristic of the inventtdd, the coating lor the modified release of the active principle with low solutô%rm#^<if:Ê8ÎC,

According to another notable characteristic resulting from: the preparation, of the microcapsules, the active principle la deposited onto foe core by techniques known to those skilled In the art, tor example the fluidised air bed spray coating technique, wet granulation, compacting, extmsion-spheronfoatlon, etc.

Aduantageottey, the icoating of foe mierocapsules may compose, in addition to foe essentia! constituents A and Í, other conventional ingredients known by those skilled in the art, such as, in particular: o colorants, o plasticizers, for Instance dihutyl sebaeate, o hydrophilic compounds, such as for example eeiulose and derivatives thereof or polyvinyl pyrroiidone and derivatives thereof, o and mixtures thereof

Without itlÄgilimiting Ä aocoilmg tu an even more prefered embodiment, foe coating of the microeapsules with modified release of active pri.ue.tpkv comprises a single composite AB coating fim, in quantitative terms, the monolayer of coating can represent, for example, at most. 4t)%, preferably at most 30%, by weight of the nticrocapsules. Such a limited degree of coating makes it possible to produce pharmaceutical units each containing high dose of active principle, without exceeding a size that is totally unacceptable with regard to swallowing. This can improve the compliance and therefore the success of the treatment.

The release triggering mechanism of the active principle xvith lew solubility, without any variation in pli. after a predetermined residence time in the stomach results in particular from the control of the hydration rate of the roierocapsules and/or Iront the dissolution of one or mrire components of the microcapsules, For example, and without wishing to be limiting, the hydration of the mkroeapsule can he controlled: o by the presence, in the mieroeupsuies, ol hydrophilic products which make it possible to adjust the osmotic pressure or to cause swelling of the mkrocapsuks; o or by adjustment of the coating film water-permeability; o or by creation of ratcroporosky in the coating film; Q or even by hydration or dissolution of a coating film compoppi!.

One of the determining advantages of the multimicroe&amp;psole pharmaceutical system with delayed and controlled release of active prinoiple(sV-for example of prinviplefs) with low solubility-according to the invention» is to involve. In vivo, two factors that trigger the release of the active pri net pici s}~~ tor example of the principk(s) with low solubility-in the gastrointestinal tract. Leo ~ the residence time in the stomach: "fime-tri ggereC releases - the variation, in pH: ''pli-triggered’’ release.

These two factors that trigger the release of the active principie(s?—for example oi prineiple(s) with losv solubility—are in series, such that they confer very sale use on the pharmaceutical system. The release k the .mot priocmkys'kkr example of the puoeiphns) xvk.t low solubiUty-ris thus ensured after a preset by time, ex en ii the ρ,Η χ ark?km hew not oeeureu as a triggering factor. The problems of interim!!vidua! variability are thus overcome. The therapeutic efficacy of the medicinal; protlnet comprising such pharmaceutical system m ensured, observing a predetenuined: e|ropohioiogy adapted m the targeted therapeutic performance.

In addition, for any active principle t'e.g, with, low solubility) with an absorption window limited to the upper parts of tic gastrointestinal tract, it is particularly advantageous for the form with delayed and then prolonged and controlled release to comprise a plurality of mierocapsules. Indeed, for such a pharmaceutical form, the dose of active principle (e„g. with low sokbúk i to be admtr étered is divided up between a large number of microcapsules (typically 5,000-30,000) and, as a result, exhibits the following intrinsic advantages: a T he residence time of the microcapsules hi the upper paris of the gastrointestinal tract can be prolonged, which ensures an increase of the time spent by the active principle with low solubility in front offne windows of absorption, and thus maximizes the bioa variability of the ueooe principle wt!h low v,-iuh'llt\, o Using a mixture of mlemeapsuies having different delayed and controlled release profiles provides release profiles exhibiting several xxaves of release P resulting, by suitable adjustment of the various fractions, in a constant level of plasma concentration of the active principle with low· solubility. o The variability in gastric emptying is mduccd, since the emptying which here takes place overaiarge number of particles is statistically momanprodueihle. o Contact between the tissues and a high dose of active principle with low sohiSUhy, "dose dumping", is prevented. Each microcapsule indeed contains a very low dose of active principle with low solubility. The risk of tissues deterioration due to a local overconcentration of aggressive active principle with low solubility is thus avoided. o It is possible to provide these mieroeapsules in the form of a sachet a capsule or a tablet. When the dose of active principle with low solubility is high ($00 mg or more), the monolithic forms have too large size to be easily swallowed. It is then particularly advantageous to have a mieroparpealate form which ensures the delayed and controlled release of foe active principle (in particular with lew solubility) and that those skilled in the art can produce in the form of dlsintegratablc tablets or sachets*

The multimicroeapsule pharmaceutical system according to the invention makes it possible to ensure, in a reliable manner, delayed and controlled release of the active principle with low solubility In the gastrointestinal tract, by virtue of two triggers, and thus to avoid the inter-and intra-individual variability of the gastric emptying conditions, while at foe same time being economically viable and easy to ingest (optimized compliance).

Another subject of the invention relates an oral medicinal product, comprising a plurality of microcapsules with modified release of active principle! s), at least some of said microcapsules individually consisting of a microparticle comprising at least one active principk—in particular at least one active principle with low solubility-fovith the exclusion of carvcdilol). coated with at least one coating for the modified release of the active ptincipieCs), said release being controlled by two distinct triggering mechanisms, one based on a variation in pH and the other allowing release of foe active principle(s) after a predetermined residence time in foe stomach, said coating; 8 also conferring on the microcapsules an in vitro dissolution behavior (determined according to the indications of the European Pharmacopoeia, 4th. edition, entitled; ‘'Dt.V'Vhttion fost tor Solid Oral Forms"; type H dissolûtes! performed under SINK conditions, maintained at 37,degree, C. and stirred at 100 rpnri such that; * at constant pH 1.4, the dissolution profile comprises a lug phase less than or equal to ? hours, preferably less than or equal to 5 hours, and even more preferably between 1 and $ hours; « at least $0% by weight of the active ptincipieCs) is released aber !<> h at pH 1,4; » the change írom pH 1.4 to pH 7.0 results in a release phase that begins without anf !!§ time; * and comprising a composite material comprising at least one hydrophilic polymer A carrying groups that are ionized at neutral pH and tu least one hydrophobic compound B; this medicinal product being characterized * in that at least some of said rnicrocansules comprise at least one release helper capable of increasing the permeability of the coating for the modified release of the active principle(s), * and in that, the weight .traction of foe active principle!» released during the lag phase is less than or equal to 15% by weight per hour, preferably less than or equal to 10% by weight per hour, and even more preferably less than or equal to 5% by weight per hour.

In fact, it appeared to be useful in accordance with the invention to provide for, in the mlorocapsuies,: one or more helpers suitable for increasing the permeability of the coating, so as to reduce the release time for in particular active principles with low solubility. helper consists of at least, one swelling agent, as helmed shave.

The medicinal product according to this other subject of the invention is also remarkable in that the coating of the microcapsulev included in this medicinal product confers on said mi croc apsides an in vitro dissolution behavior (determined according to the indications of the European Pharmacopoeia, 4th edition, entitled: "Dissolution Test for Solid Oral Forms": type II d'sso'cc si ne i vmet <5îdt‘ M\k s · J'tiocs, ms c, '> ad at 3 ” oectee R wv starred ai 1 > ) rpni), such that at least Sill by vv^fghi of the adtlipiieipteis) isfefeased aiar Ilit at pH 1.4

The fact Ihat the medicinal product according to the invention consists of a plurality of mkroumts makes it possible to obtain another essential characteristic of the invention, according to which the medicinal product comprises a mixture of various populations of microunits containing active principles) (with the exclusion of carvedrlol), these populations differing from one another by virtue of their respective in vitro dissolution profiles, for at least one pH value of between 1,4 and 7.4,

This essential characteristic makes it possible to obtain an increase in the bioahsorption time tor the active principlets) and therefore in the tinte during which the plasma concentration is greater than the minimum effective concentration of this active principle.

In tact, the mixture of various populations of microunits (e.g, nticrooapsulos with modified release of active principle and, optionally,, microparticles with immediate release of active principle) results in a preferential release of the active principle(s) at different sites in the gastrointestinal tract, over the entire extent: of the bioahsorption -viad«' -of -Ä# principle(s) in the gastrointestinal tract.

According to an advantageous embodiment of this characteristic of mixture of varidps populations of microunits, the medicinal product according to the invention is characterised in that the miermmits are microcapsules with modified release of active principle^) and, optionally, microunits with immediate release of active princip!e(s>.

Advantageously, the populations of microcapsules wit|.||od||cd wl%$sa· |dipe J$lncipl<îf dilfer by virtue of their n. speeds e triggering pIR 1 he popukox'UN oi rnuunvewulcs w tit moot fed release net's e prie,;· ip Vo A can differ not only by virtue of then »cvcawc ngge og pHs, but also by virtue rtf their respective triggering times, or even of their respective triggering pHs and times.

According to a preferred etoktdlmeuf of this Agaeleristie pf mixing populations, the medicinal product comprises: l at. least one population of microunits containing active principle with huMedlafe releases h, at least one population Pi of microeapsules with modified release of active principle(s); and hi. at least one population P2 of microeapsules with modrled release of active prineiple(s)', and, moreover, the respective triggering pHs of FI and P2 differ by at least 0,5 pH unit, preferably by at least (>.$ pH unit, and even more preferably by at least 0.9 pH unit.

According to a preferred arrangement relating to the triggering pBs that differentiate the various populations of microcapaules with modified release of active pnneipie(s), said; respective triggering of pHs are between 5 and 7.

According to another variant of the preferred embodiment of this ohahteteristic of mixing populations, the medicinal product comprises; i. at least one population of microunits containing active principled) with immediate release; il at least one population ΡΓ of mi croud ts containing active principles), made up of mieroeapsules with modified release of the active principle(s), the triggering pH of which is equal to S.S; and on at least one population P2* of mieroimits containing active prineiple(s), made tip of mieroeapules with modified release of the active principle(s)5 the triggering pH of which is equal to 6.0 or 6.5.

The release profile (measured in an in vitro release test as defined above) of the microcapsules with modified release used in the abovemeniioned mixtures of various populations of mieroimits (for example Fl &amp; F2 or PI5 &amp; P2’> may be, for example, as indicated below: * less thug 20% of the acti ve principleCs) is released alter 2 hours at pï 1—1.4;

« at least 08% of the active panciple(s ) Is released alter 16 hours at pH« 1 A

When the medicinái product according to the invention comprises at least one population of mu returns antammg aebst. prmwokts) with immediate release, this population can advantageously be defined by its behavior in an in vitro dissolution test, said behavior being such that at least 10% of the active prineiple(s) is released within 1 hour at a pH between 1.J and 7.4.

According to an advantageous characteristic of the invention, the proportion of active principles*) with tow solubility in Ute microunits containing active principes} (expressed as % by weight on a dry weight basis relative to the total mass of the mtcrounns) is between 5 and SO, preferably between 10 and 70, and even more preferably between 15 and 60.

Preferably, the orictounifs containing active principles) with immediate release are uncoated microparticles.

Without wishing to be limiting, it should nevertheless he underlined that the medicinái product according to the invention is particularly advantageous in that it can be provided in ibrm of a single oral daily dose comprising * from 5,000 to 50,000 microunits containing active prlneipiefst, or * from 5.000 to 50,000 microcapsules with modified release of active pnncipie(s),

This plurality of microcapsules, illustrated by the numerical examples mentioned above, constitutes a pharmaceutical form that is entirely well tolerated by the mammalian organism.

These microcapsules are all the more advantageous since they ate manufactured simply and economically according to techniques well known to those skilled in the art, lor example the fluidized air bed spray coating technique, wet granulation, compacting, extrusion-spheroniza tiop, etc.

For further details regarding the preparation of these microcapsulcs, it) particular in their embodiment with a neutral core coated with at least one active layer comprising active principes) and with at least one outer coating ihr the modified release ot the active principle's), reference will he made to the cornent of PC'F application W0~Â-f R 03d)3OR 7 S „ whose content is integrated into the present disclosure by reference.

The medicinái product in the multimicroparíicuiate oral pharmaceutical forms according to the invention can he a tablet, advantageously an orally dispersible tablet, a powder, a liquid suspension or a capsule containing rnierocapsuies. in other words, this medicinal product cart be provided in the form of a sachet of rnierocapsuies powder, of a liquid suspension of rnierocapsuies, of a tablet obtained from rnierocapsuies or a. capsule containing rnierocapsuies.

These tablets, capsules, powders and suspensions may consist of mixtures of the various populations of microunits, and in particular of rnierocapsuies of active prlncipie(s) according to the Invention, preferably combining therewith microumts or microparticles vedh immediate release of active prim-pie with low solubility (for example grannies).

Moreover, the invention is directed to the use oi the rnierocapsuies with modified release of the active prineiple(s) as defined above, and, optionally, of the mi emun Its containing active principlefs) with immediate release, for 'he preparation of pbamxu eot'.eai or ùeteoc mkroparticuiate oral dosage forms, preferably in the form of tablets, which arc advantageously orally dispersible, powders or capsules.

Furthermore, the invention relates to the rnieroeapsutes as defined above, italén as such,

Preferably, the active pnneinle(s) may be chosen front at least one of the following major varieties of active substances, e.g.; antiulcer agents, amidiabetle iapnii anticoagulants, autithromhics, blood lipid-lowering agents, anfiarythmics, vasodilators, anti-angina agents, antihypertensives, sasoproteethe agents. iettiktr promoters, inducers and inhibitors of uterine labor, contraceptives, antibiotics, antifungal agents, antiviral agents, anticaneer agents, anti-in.fiantmatO.ries, analgesics, aniiepiieptks, antiparkinsonian agents, neuroleptics, hypnotics, anxiolytics, psyehosthmdants. anthnigralne agents, antidepressants, antitussives, antihistamines or antiallergic: agents, agents for combating congestive heart, failure, angina pectoris, left ventricular hypertrophy, cardiac aryihtnias, myocardial infarctions, reties tachycardia, ischaemic heart disease, atheromatosis, hypertension rotated to diabetes mellitus, portal hypertension, dimness, bradycardia, arterial hypotension* hydrosodic retention, acute kidney failure, orthostatic hypotension and cerebral congestion, .and mixtures thereof.

As examples of active principles that may be contained in the medicinal product, according to the invention, mhption may be made of those selected from the group of the following compounds; acctylsalicyiie acid, carbamazep.me, pentoxifylline, prazosin«, acyclovir, nifedipine, dihiaaem. naproxen, Ibuprofen, fitabiprofen, ketoprofen, fènoprofen, indantefhaein, diclofenac, feniiazac, oestradiol valerate, metoproloh sulpiride, oaptopril, etmendine, zidovudine, nicardipine, terfenadtne, atenolol, salfeutamok carbamazepme* ranitidine, enalapril, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, spironolactone, S-asa, quinidme, perindoprih morphine, pentazocine, paracetamol, omeprazole, lansoprazole, metoeloprarm.de, aminosalicylic acid, nalidixic add, amoxicillin* amoxicillin and potassium clavulanate, ampicillin, ampicillin and sulbactam, azithromycin, bacampieillm, carbeniciHin intianyl sodium (and other earbenieillln salts), capreomycin, cefiuiroxil, oefazolin, cephalexin, eephalothin, cephapirin, cephacelor, cefproxi.l cephadrioe. eelkmandoie, oeíonieide, eetoranide, cefuroximc, eefixiroe, cefopenaxoise, cefotaxime, Cefpodoxime, eeftaxidime, ceftibuten, oeftixoxíme, ceftriaxone, cefepimo. cefmdazole, eefoietan, cefoxitin, Ciprofloxacine, clarithromycin, eHndaraycin, ctofaaimine, cMxaeiliin. comamoxMOle, cycloserine, didoxaelilin, dirithromycln, erythromycin (and erythromycin salts such as estokne, ethylsuecinate, glaceptate, lactobionate, stearate). ethamhutoM-ICi and other salts, ethionamide, fosfomycin, imipenem, Isoniazide, levofloxadne, lornefioxacine, loraearhefi .methicifiirt, rnsthenamine, metronidazole, oietoelopramide, mezlocillin, nafcIHin, mti'ofnrandin, norfloxacin, novobiocin. ofloxacin, oxacillin, penicillin V. penicillin salts, penicillin complexes, pentamidine, piperacillin, piperacillin and tazobactam, sparfiox&amp;ein, sulphacytine, suiphamer&amp;rine, suiphamethaxlne, sulphamethixote, sulphasalazme, sniphisoxaxole, sulphapyrizine, sulphadrixlne v'phocthox > ' -, si riap^m c, ΐιοηκϋϋη, ticarcii Hn and potassium clavul&amp;natc. trinnrthoprime, trimetrexate, iroleanomyeuv vaneomyehp verapamil and mixtures thereof

According to a particular but non limiting variant of the invention, the active principk(s) is (are) one of the active ptiticipleís) with low solubility, for example chosen from the active principles as mentioned above (taken by themselves or as a mixture with one another),.

The active principles to which the present invention also relates may also be nutritional and-or dietetic supplements or mixtures thereof, such as, for example, vitamins, amino acids, antioxidant.- or fiaee elements, or nu\ tores thenv.

Finally, the invention is also directed to a method of therapeutic treatment, characterized in that it consists of oral administration, according to a given dosage, of the medicinal product, according to the invention as defined above.

The invention will be explained more thoroughly, by the following examples, given solely by way of illustration in order to fully understand the invention and to reveal its variants of implementation and/or of use,

EXAMPLES

DESCRIPTION OF THE FIGURES FKL i: In vitro release profiles of the microcapsuies prepared according to Comparative Example 1, ΠΟ. 2: In vitro release profiles of the microcapsules prepared according to Cooperative Example 2·. FIG. 3: In vitro release profiles of the microcapsuies prepared according to Comparative Example 3, FIG. 4: in vitro release profiles of the accord^:# Comparative

Example 4..

FIG, 5: in vitro release profiles of the microcapsuies prepared according to Example 5 and comparison with the release profiles of die microcapsuies prepared according to Comparative L FIG. 6: In vitro release profiles of the microcapsuies prepared according to Example 6 and comparison with the release profiles of the micmcupsuies prepared iccording to Comp.uvtfiu y FIG, 7: In vitro release profiles of the mlcröcapsuies prepared according to Example ? andi comparison with the release profiles of the rpicrocapsoles prepared according to Comparative 3. J: IG. B: Release profiles of the mictmspfc paparad. according to Examples 8, 9 and 10 at pH 1.4. PÍG. 9: Release profiles of the mictocapdesipg^red according to Examples 8. 9 god lil measured for 2 h at pl 1 1 ,4 and then at pH 6.8, FIG, 10:. Release profiles of the mkrocapsdes prepared according to ! xamptes 10. i 1,12 and 13 at. pH 1.4, FIG, 11: Release profiles of the nioroeapsules preparedIMidmg to Example 14, FIG, 12: Release profiles of the tPkrooapsules prepared according to Example 15. FIG. 13: Release profiles of theliicrocapadcs prepared according to Example !6> FIG, 14: Release profiles of tMülwocapsales prepared according to Example 17, lie exasu|les:;heltxw^

Comparative Example 1 (spironolactone). Comparative Example 2 (amoxicillin, trihydrate}. Comparative Example 3 (nitrofurantoin) and Comparative Example 4 tearvedilo!) illustrate formulations with delayed and controlled release of the active principle, obtained according to WO-A-03/03878, However, it would he advantageous to conserve the lag phase while at the same time increasing the release rate after the lag phase, m order to optimise the bioavailability and the efficacy of the active principle. The mierocapsnlcs of Comparative. Examples I to 4 do not comprise any swelling agent.

Examples S (spironolactone}, 6 (amoxicillin trihydrate) and 7 (mtrofinnntoin) illustrate formulas according to the invention,

Exarngtes 8,9 and 10 (acyclovir) show the influence of the amount of swelling agent prisent In tire formuias on the release kinetics at pH 1,4.

Examples I f, 12 and 13 (acyclovir) illustrate a nonmxbaustive selection of swelling agents that may be used in the formulas according to the invention.

Example 14 (acyclovir) illustrates: the preparation of ndcroeapsdles combining a wet granulation step and a coating step in a fluidized air bed.

Exemple 15 (acyc lovir) illustrates the preparation of microcapsules comblping :¾ extnrsion/spheromzaiion step and a coating step in a fksidixed air bed.

Example 16 (acyclovir) Illustrates the preparation of microcapsules combining a compacting step and a coating step in a fluidized air bed.

Example 17 (acyclovir) illustrates the preparation of a medicinal product composed· ö!,th&amp; mixture of various tspes of microunits.

Comparative Example 1 : Preparation of Mierocapiules Ä SpircÄdlÄOPi: "CôftîaiaÈifp ï% Swelling Agent

Step 1: 432 g of spironolactone ami 48 g of low molar weight byGroxypropyiceUoiose (Klocel™ EF/Hercules) are dispersed In 1120 g of purified water. The suspension is sprayed onto ?2i g of neutral nriorespheres (Asahu Kaséi) in a Glatt GPCG1 spray eoater.

Step 2: 4322 g of hydrogenated cottonseed oil (Penwest) and 64.8 g of poíy{methaerviicaciáXethyí acrylate'} F:udragifm 1,100-55 (Rohm) are dissolved under hot conditions iu tsofopanol Fhe solution is sprayed onto 492 g of microparticles prepared above.

The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 3/.degree, C. and with stirring at 100 rpm, ín the following media: - HC1 at pH 1.4 ·* HCi at pH 1.4 for 2 hours aplthen KHjPO^/NaOH buffer medium at pH 6.8.

The dissolution profiles are given in FIG. 1. it is noted that: ~ at pH 1.4, the release of the active, principle is slow alter the lag period of approximately 2 hours; - when the pH changes from pH 1A to pH 6.8, the release kinetics accelerate but remain: slow (approximately 8 hours rue required to release 80% of the active principle).

The tim'd compositions according to the intention make h possible m accelerate the release profiles at pH 1.4 and at pH 6,8, white at the same time conserving the lag phase: at pH 1.4.

Comparai h e Example 2 : Preparation of Cricrocapsules of Amoxicillin Trihydrate Containing No Swelling Agent

Step 1 : 1620 g of amoxicillin trihydrate and 180 g of low molar weight hydmxypropyieeliulose (Kiueelm EF (Hercules) are dispersed in 4200 g of purified water. The suspension is sprayed: onto 2.00 g of neutral mkrospheres {Asahi-Kaséi) in a Glatt GPCG1 spray coater,

Step 2: 120 g of hydrogenated cottonseed oil tPe.nwest) and 180 g of polyCmethacrylic ack!)(eihyi acrylate) Acrycoat™ UG0D INF Pharm) are dissolved under hot conditions in isopropanol T he solution is sprayed onto 700 g of microparticles prepared above, fhe mieroeapsuies obtained as. the end ¢4 she second step were tested in a type 11 dissolut esi in accordance with the European Pharmacopoeia, 4th edition, at 3?.degree. C. and wiihstimog at 100 rnm, in the ibliovdua uwdu; - HO at pH 1.4 - 1 (Cl at pH 1.4 for 2 Anns and then KlkPCXifNaOIl huiler mediunt at pH 6.8.

The dissolution profiles are given In FIG, 2. It is noted that: λ at pH 1,4. the release of the active principle is alow·· after the lag period of approximately 4 hours; :% when the pH changes from pH 1.4 to pH 6.8, fhe release kinetics axe rapid as expected.

The novel compositions according fothe: tnvsnion make M possible to optimize the release profiles at pH i A while at the same imo malnteing rapid release at pH 6,8 and conserving a- lag phase at pH ! .4,

Comparative Example 3 ; 1hPpar#ton of Miorobapp.iIes irf iHitp.f\tfahtoi|i. .tionlaininf 'Ho Swelling Agent

Step i: 640 g of amoxicillin trihydrate and 160 g of low molar weight hydroxypropylcellulose {Klucel™ BF/Hercules) are dispersed hi 2400 g of purified water,. The suspension is spiauM onto 200 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCGI spray coat er.

Step 2f 40 g of hydrogenated cottonseed oil {Penwesth 5 g of dibutyl sebacate (Morfiex) and 55 g of polyCmethacrylk: add)(ntefhyi methacrylate) EudmgitTM l,100 (Rohm) arc dissolved under hot conditions in Isopropanol. The solution is ^ptayeo owe °00 ot v v opatOdc^ n epared above,. lire microcapsules obtained at the cod of the second step were tested in a type 11 dissolûtes! in accorda ve with the t uepcae Pharmacopoeia, 4th edition, at 3?,degree, C, and with stirring at 100 rpm„ in the following media: - HClatpH 1.4 - HC! at pH i .4 for 2 hours and then KIT Ft \, NaOi 1 buffer medium at pH 6.J,

The dissolution profiles are given in FIG. 3. It is noted that: - at pH 1.4, the release of the active principle is slow after the lag 2 hours; - when the pH changes from 1 4 to b.8. the release kmc ties am rapid as expected.

The novel compositions according to the invention make it possible to optimise the release profiles at pH 1.4, while at the same time maintaining rapid release at pH 6,8 and conserving-a lag phase at pH i .4,

Comparative Example 4 t ^reparation of Mkrocapsules of Carvedilol Phosphate Containing No Swelling Agent 1120 g of earvedllo! phosphate and 280 g of Plaolone K29/32™ (ISP) are dispersed in 1120 g of purified water. T he suspension is sprayed onto 60â g of neutral microspheres (AsahhlCasct) in a Clatt GPCGÎ spray comer, 100 g of hydrogenated cottonseed oil (Peawest) and ISO g of Eudragit™ LI 00*55 (Rohm) are dissolved under hot conditions in Isopropanol, The solution is sprayed onto 750 g ot microparticles prepared above.

The microcapsules obtained at the end of the second step were tested in a type 11 dissolutest in accotdatue with the Pharmaeopoe'u. at 37 degree C and with stirrmg at 100 rpnp in the following media:: - HClatpH 1.4 - HC1 at pH ί .4 for 2 hours and then KlVCl^fNaOH bufter medium it pH 6.8 Üb dissolution profiles are gives în FIG, 4 In the appendix. It Is noted that: - at pH 1A the release of the active principle is slow after the lag period oi approximately 2 hoots; - wlten tire nil ihanpsifom 1; ,4 to 6J» therelesse kinetics accelerate but remain slow (at 16 hours, only 40% of tie active principle has been released).

Ikample JIt Preparation <»f Microcapsuies of Spironolactone According to the Invention Step I ; 216 g of spironolactone, ?2 -g of low molar weight hydroxypropylcelInlose (KluceP* Blkllercules). 72 g of PEO»4Ö hydrogenated castor oil {CremophorRH 40/BASF) and 360 g of crospovidone *ÍKoÜidon CMUSH are dispersed in 1120 g of purified water. The suspension is sprayed onto 720 g of neutral microspheres (Asahi-Kasei) m a Glatt GPCGI spray coaler.

Step 2; 43.2 g of hydrogenated cottonseed oil (Penwest) and 64,8 g of noly(methaerylic acid)(eihyt acrylate) Budragitm Li00*55 (Rohm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 492 g of microparticles prepared above.

The microcapsuies obtained at the end of the second step were tested .n a type 11 dissolûtes', hi accordance with the European Pharmacopoeia, 4th edition, at 37.degree. (.., and with .stirring at 100 rpm, in the to 1 lowing medlar ·· HCi at pH 1A - HCl ai pH ! .4 tor 2 hours and then KHjPiVHaOH bufifer medium m pH 6.8

The dissolution profiles of Example 5 end of Compamive Example I are given in FKM* It is noted Utat; - at pH 1,4, approximately 60% of the active piuelpie is released aier a lag period of approximately 1 hour 30 min; *· when the pH changes from 1A to 6.8, the release kinetics sarc rapid.

Example 6 ; Preparation of Microcapsuies of Amoxicillin frihydratc According to the Invention

Step 1 : 6k' i ol umoxiedht Ho* ,v, 96 <. xw done p asdom''M f JSP)) and 180 g of erospovidonc ( P o Kid asdo noT % ISF ) are dispersed in 2100 g of isopropanol-Hater {70-30 nvm) mixture. The solution is sprayed onto 100 g of neutral microspheres (Asahi-Kasei) in a GlattrM GPCGI spray coater,

Step 2: 120 g of hydrogenated emtonwed où ; hbrtee) and 160 g of polyimeiMenhc a.C(di(edo * acnhnel K.olHeoatïM M \l 100P VBASF' arc dissolved under hot condttvns m Isopropanol The solution is sprayed onto 70(.) g of microparticles prepared above.

The nuemeupsuks obt ened at the mi of dv second step wore tested n, a n jx 11 c.ssoosteat ,n accordance with the European Pharmacopoeia, 4th edition, at 37.degree, €, and with stirring at 100 rpm, in the following media; - HCI at pH i.4 » BQ dl pH 1 A for 2 hours and then KlfeFOà/NâOH buffer medium at pH 6.8

The dissolution prod los of Example 6 and of Comparative Example 2 are given in FIG. 6. It is noted that, with the composition according to the invention: - the .release of the active principle at pH 1.4 was accelerated (ensuring triggering ol the system alter a given time and release of a sufficient amount of active agent, this release taking place over imnw eompanhe w,th the ab»nuvon ' ms or tic Λ ve p* t ones im organism); - when the pH changes horn ! ,4 to 6J, rapid release kinetics arc maintained,

Example 7 : Preparation olMierÄpsoles ofHitroűnmlom According to the Invention Step 1: 40Ö g of nitrofurantoin, 200 g of povidone (piasdone™ K.29/32/1SP). 50 g of PECHi hydrogenated castor oil (BASF) arai 350 g of erospovldone {folypUtsdoac™/ISP) are suspended in 2500 g of purl lied water. The solution is sprayed onto 1000 g of neutral microspheres (Asahi-KaseO In a Glatt™ GPCG1 spray coater.

Step 2: 120 g of hydrogenated cottonseed oil (Abiteo) and 160 g of polyfmethacryiie acid}(ethyl acrylate) Aeryeoat™ L10OD (HP Phann) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 700 g of microparticles prepared above.

The microcapsuics obtained at. the end of the second step were tested in a type II dissolûtes! In accordance with the European Pharmacopoeia, 4th edition, at 3/.degree. €. and with stirring at UK) rpm, in the following media: ~ RCIat pH 1.4

*.= MCI at pH ! .4 for 2 hours and then KHffiCTpHaGH halier medium at pH 6 J lie dissolution profiles of Example ? and of Comparative Example 3 are given m FIG. 7, It is noted that, with the composition according to the invention: - the release of the active principle at pH 1,4 was accelerated (ensuring triggering of the system after a given period of time and release of a sufficient amount of active agent, this release taking place over times compatible with the absorption times for the active principles in the organism); - when the pH changes fmm ! ,4 to IJ, rapid release kinetics am maintiihed.

Comparative Example 8 i Preparation of Microeapsuies of Acyclovir Containing No Swelling Agent

Step 1; 7$ g of acyclovir and 75 g of povidone (Plasdone™ É.29/32/ÍSP ) are dissolved in 833 g of Isopropanol The solution '® spafed onto till g if neutral mlerospheres (MF FharmT ln a Glatt™ GFCG3 spray coaler.

Step 2: 93.3 g of hydrogenated soybean oil (Abitec) and 140 g ol poly(methacryiic· acklXmethyl methacrylate) Eudragit™ LI00 (Rohm) are dissolved under hot conditions in Isopropanol The solution Is sprayed onto 701» g of microparticles prepared above.

Example 9 : Preparation of Microcapsdles of é&amp;$4mè ContmningM Étnall MmmM M Swelling Agent (Crospovkiooe™)

Step 1 : 3?S g of acyclovir, 50 g of low molar weight hydroxypropylcellulose (Klocel™ BF (Hercules)} and ?$ g of erospovidone fPoîyplasdone™/l.SP) are suspended In. 1200 g of purified water. The solution is sprayed onto 500 g of neutral mtcrospheres (NF Pharm) in a Glatt™ GPCG3 ςρτην comer.

Step 2: 100 g of hydrogenate# eottonseed oil f&amp;west) and 150 g of polytmethacrylie acid)(ethyl acrylate) Budragit™ Li00-55 (Rohm) are dissolved under hot conditions in ethanol. The solution Is sprayed onto fSO g of microparticles prepared ahem

Example 10 : Preparation of Mieroeapsules of Acyclovir Containing a larger Amount of Swelling Agent (Crospovidone™)

Step. I;: 300 g of acyclovir, 50 g of low molar weight hydroxypropyleeliulose, Kiucel™ EE (Hercules), and 150 g of crospovidone ( Potyp1asdo«e™/lSP) are suspended In 1200 g of purified water. The solution is sprayed onto 500 g of neutral microspheres (HP Pharm) in a Glatt™ GPCG.3 spray coûter.

Step 2: 100 g of hydrogenated cottonseed oil (Penwe$0 and 150 g of polyimethaerylie aeid)(ethyi acrylate) Eudragit™ LI00-5.5 (Rohm) ate dissolved ander hot conditions Ip ethanol. Ihe solution is sprayed onto 750 g of microparticles prepared above.

The mieroeapsules obtained at the end of the second step in Comparative Examples 8, 9 and 10 were tested in a type 11 dissolute in aeeordanee with the European Pharmacopoeia. 4th edition, at 3 7, degree. C, and with stlrrina at Í0Ö rpm, in the following media;

♦ HCtatpHIA ~ HCI at pH IJfe::2 horns^ and;then :RH|P04./HaDH btrier medium at pH 6,8

The dissolution pro lues of Examples 8,0 and 10 are given in FIGS. 8 and 9, It is noted that: * a broad kinetics range can be obtained at pF! 1.4 depending on the amount of swelling agent incorporated into the formulation: - ihe release at pH 6.8 remains rapid whatever the eotnposltlon under eonsidctaion.

Example 11 : Preparation of Miiroeapsiies of Acyclovir Containing a Swelling Agent (Sodium Crosearmeilose)

Step Vi 300 g of acyclovir, 50 g of low molar weight hydroxypropylcellulosc, KLIucel™ EF (Hercules)., and 150 g of sodium croscarmello&amp;e t Ao-Di»SolTM/FMC) are suspended in 1200 g of purified water, The solution is sprayed onto 500 g of neutral microspheres (NP Pharm) in a Glatt™ GFCG1 spray coaler,

Step 2: 100 g of hydrogenated eotíonseed oil (Penwest) wé 100 g of pöty(methaerylie aeidKethy! acrylate.) Eudragit™ 1000-55 (Rohm) are dissolved under hoi conditions in ethanol. The solution is sprayed onto 750 g· of microparticles prepared above.

Example 12 : Preparation of Mieroeapsules Of Acyliuvfr Comamlng a iweiling Agent (Elydroxypropylmethy Iceiluiose}

Step I : 500 g of acyclovir, SO g of low molar weight hydroxypmpyiceiloiose, KlneeP'^ £F (Hercules), and ISO g of hydraxypmpylmethylcelMose (Fharmacoat 615/Shin-Etsu) are suspended in 1200 g of perilled water... The solution is sprayed onto -500 g of neutral microspheres (NP Pharm) in a Olatf5'^ GPCG1 spray coaler, 100 g of hydrogenated cottonseed cal (Pern-vest), 100 g of polytmethaerylic acid g ethyl acrylate) Bndragh™ 1,100-55 (Rohm) and 50 g at pohpnethacrylic acidgmethy! methacrylate) Eudragit™ $100 (Rohm) are dissolved under hot conditions in ethanol. The solution is sprayed onto 750 g of microparticles prepared above.

Example 13 ; Preparation of Microcapsules of Acyclovir Containing a Swelling Agent (Povidone of Molar weight Mw~ 1,000,000 g/mol)

Step I: 350 g of acyclovir, 50 g of low molar weight hydro.xypropyk-dlo.lose (RincerM EF (Hercules)) and 100 g of high molar mass povidone (Kollidon™ 00 (BASF)} are suspended in 1200 g of purified water. The solution is sprayed onto 500 g of neutral microspheres (NR Pharm? in a Ghtt™ G PC Oi spray coaler.

Step 2 : 100 g of hydrogenated cottonseed oil (Penwest), 50 g of polyimelhaerylic acid)(othyf acrylate) Eudragit™ LI00-55 (Rohm) and 100 g of po!y(nuMtaery.lk ac,ld)(meth)d methacrylate) Padragit™ SIÔ0 (Rohan are dissolved under hot conditions in ethanol Th® solution Is sprayed onto 750 g of microparticles prepared above.

The nhcrocapsuks obtained at ibe vnd of the second step oi Examples 10,11,12 and 13 were tested in a type 11 dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37,degree, €. and with stirring Ο.Π00 rpm at pl i 1.4.

The dissolution profiles arc given In FIG. ft

Example 14 ; Preparation of Microcapsoies of Acyclovir Containing a Swelling Agent (Granulation·!· spray Coating)

Step U 700 g of acyclovir, 50 g of povidone {l%sdone™/lSP? and 250 g of crospovidoeS; tPolyplasdone™/iSP) are dry-mixed beforehand in a laboratory granulator (Ledige) for b minutes. This pulverulent mixtum is then granulated with water (200 gh The granules &amp;&amp; dried at dO.degre-c. €, in a ventilated oven, and then sized on a 508 gm screen. The 200-5Û0 gm fraction is selected by sieving.

Step 2: !ɧ J;/0f hydrogenated palm oil filais), 10Ö g of polyimethacrylie acid)(elhyl aeiudat|) Acrycea#* LI 000 and 50 g of pohimtlhaeryhc .undft methyl meducrylato \eryceafM SI OB §0. Pharm) are dissolve uáfe hot conditions in Isopropanol. The solution is spayed onto75flg of microparticles prepared above,

The micfdeapsules obtained at the end of the second step of Example i 3 were tested in a type H dissoletesl in accordance with the Eoropean Phàrmacopoildÿ 4th edition, at 37-degree, O, and with stirring at .100 rpm, in the following media: - HO at pH 1,4 - HO at pH E4 for 2 hours and then KHH^NaCil fetÄf medium at pH 6,8u The dissohdien profiles are given In FIG, 11.

Example 15 : Preparation of Miemeupsules of Acyclovir Containing a Swelling Agpl (Extrusion/Spherorüxaüon "'· spray Coating)

Step 1 : TOO g of acyclovir, .50. g of povidone tPiasdone^ViSP! and 250 g of crospovidone (K,olHdo«m CL2BASF) are premixed with 150 g of mater in a laboratory mixer (Kitchen-Aid) for 5 minutes- This pasty mixture is extruded through a 0.5 mm screen using an Extruder 20 (Caleva), The ^laments obtained are then spheronixed using a Spheronixer 250 (Caleva). The particles obtained are dried at 40.degree, €. in a Outdated air bed. 'The 300-/00 μ?η fraction is selected by sieving.

Step 2: 100 g of hydrogenated palm oil (Huls), 100 g of poly(methacryiic aeidKethyl acrylate) Acrycoat™ 1,-lOOD and SO g of polyimethaerylic acid)(methyl methacrylate) Acryeoat™ SI 00 (NP Pharm: are masoHed unda' hot conditions in isopropanol The solution is sprayed onto "50 g of miempanides prepared above.

The microcapsuies obtained at the end of the second step of Example 14 were tested in a type II dissolutest in accordance with die Pharmacopoeia, 4th edition, at 5 7.degree. €, and with stirring at UK) rpm, in the following media: - ΙΙΠ at pH 1.4 - IICl at pH 1-4 for 2 hours and then KH,<PCbdShtOH buffer módúm; at pH n 8,

The dissolution profiles are given in FIG. 12.

Example lb : Preparation of Mierocgpules of Acyclovir Cnntalpipg a Swe|ilig; Agem rÇompaclug ·;· spray Coating)

Step 1 : $50 g of acyclovir- 10 g of magnesium stearate and 400 g of crospovidone are mixed using a laboratory mixer (Kitchen-Aid type) tor S nunotes. This mixture is then compacted usutg an Aiexendenverh W FI20 Ldxsatory compactor. The ptodnet obtained is then granulated using an Erweka oscillating granulator equipped with a 500 pm screen- The 100-500 pm fraction of the product obtained Is selected by sieving.

Step 2; 100 g of hydrogenated palm oil (Buis), 100 g of polyfmethaerylie acidgethyi acrylate) Acrvcoat L100D and 50 g of polytmeihaeryhc ncidymethyl méthacrylate) ÂeryeoaH4* SI00 tNP Pharm) are dissolved coder hoi conditions in isopropanol The solution is sprayed onto /50 g of microparticles prepared above.

The microeapsules obtained at the era) of the second step of Example 14 were tested m a type il dissoUnest in accordance with the Pharmacopoeia, 4th edltkm at o/.degree, and with stirring at 100 rum, in the foil owing médiat - HCl at pH Id' · HO at pH ÍA tbh| hoars and then KI hPÖpBaÖff iller mediumlafpllf j.

The dissolution profiles are given In FIG. i 3.

Example 1? : Mixture of Microumts Having Various Release V irmas nie menus of acyciowr are prepared, tn which; - 25% by weight of the acyclovir is in the form of immediate-release microunits as obtained at the end of the first st ep of Example 12, . 25% of the acyclovir is in the form of delayed and prolpnged-release pperonnits as obtained at the end of the second step of Example 10, and - 50% of the acyclovir is in the fönn of delayed and proÂped-mfcam^»^pulm:.âs obtained at the end 01 the second swoei Example 12

The microcapsules of Example !&amp; 19 begin to r«p%mbamfafa-van/MIl· shove 0 > 5,5 ; use of Budragit™ !.. 11)0-55 ).

The nikrooapsules of Example: Ho:, 12 begin to rapidly release them content above pH1.5 (use of 67% itMmgii^ Χ10Μ5 and 33% Eudragit™ S100).

The profiles are given In FIG, 14 and show that various release phases are obtained, which optimises the relise of an aeive principle in front of its absorption window. * * * # *

Claims (8)

trifle gyógyszer legalább agy hsÄbpg módosított kibocsátására, SllliàDÂLMI:: IGÉNYPONTOK IcÖiiiilgyőgyászatí termék, amely a hatéanyag(ok) módosított kibocsátására alkalmas mikmkapszulék sokaságát tartalmazza, a mikrokapszuíák legalább egy része egyedileg olyan mikrorészecskékből áll, amelyek legalább agy hatóanyagot tartalmaznak. különösen legalább egy alacsony oldékonyságú hatóanyagét, kivéve á carvedlíöit, legalább egy, á hatóanyagok) módosított kiibosátására szolgáló beve-nattai bevonva, amely kibocsátás két különböze! kiváltó mechanizmus által szabályozott. ahol az egyik a pH-változáson alapul, a másik pedig a haiöanyagpkpák á gyemötbafi való, előre megbatározott tartózkodási időt követően történi kibocsátását teszi tibetivé, az említett bevonat pedig a mikrokapszulákon egy olyan in vitro oldödill iilWÜ kölcsönöz, hogy: - allandé.; 14 pH-értékon, az oldódási profil magában foglal egy 7-néi kisebb vagy ezzel egyenlő óra, előnyösen egy őrnél kisebb vagy ezzel egyenlő óra, és még előnyösebben egy 1 és 6 őrá közötti ídötartamó: kisiettető fázist; - az 1,4 pH-röl a 7,0 pH-ra való átmenet egy olyan kibocsátási fázist eredményez, amelynek nincs holtideje; tizÉl |lliemezves begy a milmkapzulák legalább egy része tartalmaz legalább egy: duzzadást elősegítő anyagot, és, hogy a késleltető fázis alatt kíbocsitótt batianyag{ok) tömeghányada kisebb, mint 15 tömeg% per óra, vagy ezzel egyenlő, előnyösen kisebb, mint 10 tömeg% per óra, vagy ezzel egyenlő, és még előnyösebben kisebb, mint § tömegéi per óra, vagy ezzel egyenlő . fX Az 1. Igénypont szerinti gyógyászati termék, azzal Jellemezve* hegy a duzzadást elősegíti anyag tartalmaz legalább egy olyan hidrofil győgyszerészetileg elfő-gaihiifi vegyületet, amely vízben, 25*ü-on, 10 timeg%-náí nagyobb vagy ezzel egyenlő, előnyösen 15 tőmeg%~nál nagyobb vagy ezzel egyenlő, és még előnyösebben ti tőmég|i-n|i nagyobb vagy ezzel egyenlő duzzadás! fokot matatték %.Az 1 igénypont szerinti gyógyászati termék, azzal jellemezve, a ciuz" Äsegitö anyagsíi azok kézét választjuk, amelyek egy in vitro oldódási té$z^ |en 16 Ifit kővetően., 1,4 Hírértéken, tehetővé tésiik a mikro kapszulák szármára legalább 50 tömeg% hatóanyagnak a kibocsátását, 4» Az 1, Igénypont szerinti gyógyászati termék, azzal Jeiiamez.¥#f Itégf 4 duzzadást elősegítő anyag 5 és 200 pm közötti, es előnyösen 10 és 50 μηι közötti itla-gös átmérőjű mikrorészecskék formájában van jelen,trifle medicament for modified release of at least brain hsÄbpg, SllliàDÂLMI :: IGNITES It contains a multitude of microcapsules capable of delivering the active substance (s), at least a portion of the microcapsules is individually made up of microparticles containing at least a brain active ingredient. in particular at least one low solubility active ingredient, except for carvedlite, at least one of the active ingredients) is coated with a modified release liner, which is two different emissions! trigger mechanism. where one is based on a change in pH, and the other, after the predetermined residence time for the shedding of shells, is said to produce Tibetan, and said coating on microcapsules lends an in vitro solution to: - allande .; At a pH of 14, the dissolution profile includes an hour of less than or equal to 7, preferably less than or equal to a guard, and more preferably a span time of between 1 and 6; - the transition from pH 1.4 to pH 7.0 results in an emission phase having no dead time; at least a portion of the milm capsules contains at least one swelling agent, and that the weight ratio of the batik substance (s) emitted during the delay phase is less than or equal to 15% per hour, preferably less than 10% by weight. per hour, or more, and more preferably less than or equal to the weight of § per hour. fX The pharmaceutical product according to claim 1, characterized in that the tip promotes the swelling material comprising at least one hydrophilic precursor compound having a water content of greater than or equal to 25, preferably 10, preferably 15, of weight. greater than or equal to%, and more preferably you have greater or equal swelling! The pharmaceutical product according to claim 1, characterized in that the cyano-acrylic material is selected from the group consisting of an in vitro dissolution factor of 16 Ifit. at least 50% by weight of the active ingredient, 4 "The pharmaceutical product according to claim 1, wherein Jaiamez is present. It is in the form of microparticles having a diameter between 5 and 200 µm and preferably between 10 and 50 µη. . 5. Az 1.. igénypont szerinti gyógyászati termék, azzal Jellemezve, begy I duzzadást elősegítő anyag koncentrációja (Cd) a mikrokapszulák össztömegét véve ala-pel 3 fimegH is éO tőmeglí közötti, előnyösen 4 tőmeg% és 30 tömeg% közötti, és még előnyösebben 5 tömeg% és 25 tömeg% közötti. Ü Az 1. igénypont szerinti gyógyászati termék, azzal jellemezve, begy a duzzadást elősegítő anyagot a következő termékek áiai alkotott csoportból választjuk ki: - térhálós polivlnií-pírroíidönok (például poiyplasdone vagy crospovidone), k térbálős karlözhaiklbceiiulózok. térhálós karboxi-metil-ceííulózok (például oroscar- meilose), - és hidrofil polimerek nagy moisÜyá! (nagyobb vagy egyenlő 100000 0% például: V poíiviníbpirrolldonok, * lölialkiién-oxldok (például polietilén-ovid vagy polipropiíén-oxld), * (hidroxí}(aikil)coiiuiőzok (például Ndroxi-propléceiiulóz, hldroxi-propihmetil-cellulóz), « karboxi-alkii-eeíiulózok (például karbcxxémetiPcelluiöz), » cellulózok (por vagy mikrokristályos), * módosított keményítők (például oátnum-gíikoiáitai módosított), » természetes keményítők (például kukoncakeményfiö, lulakéménptő v|gy burgonyakeményítö), * nátnurrvaíginát * poíakrilin-kálium, * és ezek keveréke, % Az előző igénypontok egyike szerinti gyógyászati termék, szarni jellemezve, bogy tartalmaz legalább egy nedvesítöszart, előnyösen a kővetkező termékek által alkotott csoportból választottat: 7-5S247/SO - anlönes felületaktív anyagok, előnyösen az a!kálif|tn-sők vagy m alkáliföldférm sók zsírsavai által alkotott alcsoportból, cdőnyősen a sztearinsav és az oleinsav, - némíonos felületaktív anyagok, előnyösen az alábbi alcsoportból: * poíioxi-etilénezett olajok, előnyösen hidrogénezett polioxi-etílénezett ricinus-olaj, * pclioxt^efilán-poiioklpropllén kopoümerek, v poíioxi-etilénezett szorbitán-észierak, * pçllqxi-etilénezelt ncinusoiapszármazékok, * pztearátok, előnyösen kaicium-sztearlt, magnézium-sztearái, alumínium-vézteeiit vagy oink-sztearát sztearil-fumarátük, előnyösen nátnem-'SZieanl-fu-marii « gíioeríl-behenáb * és ezek keveréke. fiAz eiiző igénypontok egyike szerinti gyógyászati tennék, &amp;™yeiftmezvs, begy a duzzadást elősegítő anyag a hatóanyag mikrorészecskéiben taíáíbatö.5. The pharmaceutical product according to claim 1, characterized in that the concentration (Cd) of the swelling agent of compound I, based on the total weight of the microcapsules, is between 3 and 30% by weight, more preferably between 4% and 30% by weight, and more preferably Between 5% and 25% by weight. The pharmaceutical product according to claim 1, characterized in that the swelling agent is selected from the group consisting of: - crosslinked polyvinylpyrrolidones (for example, polylplasdone or crospovidone), k spheroidal scalpel celluloses. cross-linked carboxymethylcelluloses (for example, oroscarmones), and hydrophilic polymers are high molecules! (greater than or equal to 100,000 0% for example: polyvinylpyrrolidones, lolalkylene oxides (e.g., polyethylene ovide or polypropylene oxide), * (hydroxy) (alkyl) co-solvents (e.g., N-hydroxypropylcellulose, hydroxypropylmethylcellulose), &quot; carboxy &quot; -alkyle-ethylenes (for example, carbxxx-methylPcell), »celluloses (powder or microcrystalline), * modified starches (e.g., modified with olane glycosides),» natural starches (e.g. and a mixture thereof,% A pharmaceutical product according to any one of the preceding claims, characterized in that it comprises at least one wetting agent, preferably selected from the group consisting of the following products: 7-5S247 / SO - non-surfactant, preferably a! or from a subgroup of fatty acids of alkaline earthworm salts, mildly to stearic acid and oleic acid, - silicic surfactants, preferably from the following subgroup: * polyoxyethylenated oils, preferably hydrogenated polyoxyethylenated castor oil, * pclyloxylphenylpolylopropylene copolymers, polyoxyethylenylated sorbitan esters, * p-xylethylene-treated nicotinic derivatives, * pearates, preferably calcium stearate, magnesium stearates, aluminum tetralytes, or stinkyl stearyl fumarate, preferably sodium-syano-fumarium glycolate and mixtures thereof. The pharmaceutical preparation according to one of the preceding claims, &amp; ™ yeiftmez, is a swelling agent in the microparticles of the active ingredient. 8, Az előző igénypontok egyike szerinti gyógyászati termék, azzal jellemezve, hogy a nedvesítő anyag a hatóanyag mikrorészecskéiben található.Pharmaceutical product according to one of the preceding claims, characterized in that the wetting agent is contained in the microparticles of the active ingredient. 11, Az előző igénypontok egyike szerinti gyógyászati termék, azzal jellemezve, begy a hatöanyag(ok) mlkrokapszulái egy in vitro oldódási tesztben 12 órát követően, pH~7.0 érfikin legalább 80 tőmeg% hatóanyagot s bocsátanak ki.The pharmaceutical product according to one of the preceding claims, characterized in that the microcapsules of the active ingredient (s) are in an in vitro dissolution test after 12 hours, at a pH of at least about 80% by weight of active substance and release. 11, Az előző Igénypontok egyike szerinti gyógyászati termék, Iliét latiamat ve* bogy legalább egyesek a módosított hatóanyag kibocsátású mikrokapszuíák közül tartalmazóik: - egy semleges magot, - legalább egy, a hatóanyagó{ka)t tartalmazó és a semleges magot bevonó aktív rétegek és - legalább egy bevonatot a hatóanyag módosított kibocsátására,The pharmaceutical product according to one of the preceding Claims, comprising at least some of the modified-release microcapsules comprising: - a neutral core, - at least one active ingredient containing the active ingredient (s), and an active core, and at least one coating for modified release of the active ingredient, 12, Az előző igénypontok egyike szerinti gyógyászati termék, azzal jellemezve:, begy - a hatöanyagíok) módosított kibocsátáséra szolgáló bevonat tartalmaz egy kompo- zit appg# « amely tartalmaz: - legalább egy A Ârofji polimert, amely semleges pH értéken fenééit csoportokat hordoz, legalább egy B hldrotob vegyülhet » 4§fM1ál kisebb vagy ezzel egyenlő tonieghányedet (a rolkrokapszulák te|as tömegére vonatkoztatott tömeg%} mutat lat: - a mlkrokapszuíék átlagos átmérője kisebb, mint 2000 pm. 13. A 12. igénypont szerinti gyógyászati termék, azzal jellemezve,, hagy az alacsony oídékonyságű hatóanyag; médeattst »oósátáaára szolgáló bevonat AB kompozit anyaga olyan. hogy - a B/A tömegarány 0,2 és 1,5 közötti, előnyösen 0,5 és 1J közötti - és à B hidrolob vegyulefit olyan termékek közéi választjuk, amelyek szilárd állapotban kristályosak, is amelyeknek az IVtpB olvadáspontjuk nagyobb, mint 40*0 vagy ezzel egyenlő, előnyösen m ^pB nagyobb, mint 50CC vagy ezzel egyenlő, és még előnyösebben AO^C és 9ÜÖ€ közötti. 14. A 12, és 13. igénypont szerinti gyógyászati termék, azzal Jellemezve* hogy az A hidrofil polimert a: (met)akrllsav polimerek polimerei, az aíkil~(met}akriiát polimerek, a (met)akrilsav és m elkil{met)akriiát kopolimerei. cellulóz-származékok, ceHulóz-ftalátok. celíulóz-acetát-ftatát, celloléz-szükdnáiök, cellulóz-acelát-szukeinál, hidroKipropii-metilcellulóz-ftalátok;, h Id roxipropil-metilcellaIóz~szukcin átokés ezek keverékei közül választjuk. 1§. A 12-14, igénypontok egyiké szerinti gyógyászati termék, állá! jellemezve, bogy a B vegyüieíet a kővetkező termékek által alkotott csoportból választjuk: bldrogéoézetí növényi olajok, növényi viaszok, sárga viasz, monokristályos viasz, lanolin, áohldrid tejzsir, keményzstr vagy kipaíapként alkalmazható zsír, laenNmak-rogokglicerlöok, ©etilalkohol, poilglicsrii-Oiizosztearát, legalább egy zsírsavval rendelkező glicerin diészterei és íriészterei, monoészterek keverékei, legalább egy zsírsavval rendelkező glicerin diészterei és triészteret, etilén-glikol-mcnosziaaráh dieti-lén-giikoi-monosztearát és ezek keverékei, 15. A 15, igénypont szerinti gyógyászati termék, azzal Jellemezve, itogy a B vegyiietet a kővetkező termékek éltél alkotott csoportból választjuk: hidrogénezett gyapclmagölaj, hidrogénezel szójartjagoiai, hidrogénezel pálmaőiaj, glicanhhehe-nál: hidrogénezett ncinusotaj, trisztearin, tfipalmitim ídmtrisztin, trimiristin, Omega 3 és ezek bármely keveréke. 1#, &amp; 12-16. igénypontok egyike szerinti gyógyászati termék, azzal liléméivé, hogy a hatóanyagot módosított kibocsátással blzesite mikrokapszuiák bevonata egyetlen, az AB kompozitot tartalmazó bevonófilmet tartalmaz,The pharmaceutical product according to any one of the preceding claims, characterized in that the coating for the modified release of the active substance contains a composition appg # «comprising: - at least one Abrofen polymer carrying atoms at neutral pH, at least a bulk fraction B of less than or equal to 4§fM1 (% by weight based on the weight of the cartilage capsules) is: - the average diameter of the microcapsules has a diameter of less than 2000 µm. "leaves the low-dose active ingredient; the medication for the shoulder strap" Composite B is such that - the weight ratio B / A is between 0.2 and 1.5, preferably between 0.5 and 1J, and the hydrolyz B is one of the products which are crystalline in solid form, having a melting point of IVtpB greater than or equal to 40 * 0; preferably between m ^ pB is greater than or equal to 50CC, and more preferably C ^ AO 9ÜÖ €. The pharmaceutical product according to claims 12 and 13, characterized in that the hydrophilic polymer A is the polymers of (meth) acrylic acid polymers, the alkyl (meth) acrylate polymers, the (meth) acrylic acid and the methylene chloride. acrylate copolymers. cellulose derivatives, ceHulose phthalates. Cellulose acetate phthalate, Cellulose cyclostanes, Cellulose acelate succinyl, Hydroxypropylmethylcellulose phthalates; 1§. The pharmaceutical product according to any one of claims 12-14, comprising: characterized in that the compound B is selected from the group consisting of the following products: plant oils of vegetable origin, vegetable waxes, yellow wax, monocrystalline wax, lanolin, hydrocarbon dairy spread, starch or grease to be used as excipient; diesters and esters of glycerol with a fatty acid, mixtures of monoesters, diesters of glycerol having at least one fatty acid, and triester, ethylene glycol mecrosia diethylene glycol monostearate and mixtures thereof according to claim 15, characterized in that the chemical B is selected from the group consisting of the following products: hydrogenated cotton seed oil, hydrogenated soybean oil, hydrogenated palm oil, glicanhhehe: hydrogenated nickel soot, tristearin, tfipalmitim dartristine, trimiristin, Omega 3 and any mixtures thereof. 1 #, &amp; 12-16. A pharmaceutical product according to any one of claims 1 to 3, characterized in that the coating of the active ingredient with modified release blzesite microcapsules comprises a single coating film containing the composite AB, 18. Orális gyógyászati termék, amely tartalmazza, hatóanyag(oH} módosított IfóceÉMf* JlfcaiM mtafeaps^lái sokaságát, a mikrokapszuiák közül legalább egyesek eiymagakban Ifgiíllhb egy aktiv hatóanyagot, különösen legalább egy alacsony oldékonyságú, earvedilolfóí különbóző hatőáoyapf tartalmazó mikrorészecskéből állnak, bevonva legalább egy, a hatóanyagfok) módosított kibocsátására szói-gáfö bevonattal, imily kibocsátás két különböző kiváltó mechanizmus által szabályozott, ahol az egyik a pH-változáson alapul, a másik pedig a hatianyag(ok)nak a gyomorban való, előre megbatározott tartózkodási időt kővetően történő kibocsátását feszi lehetővé, az említett levonat pedig: * a mikrokapszulákon egy olyan in vitro oldódási viselkedést kölcsönöz, hogy: - állandó, 1,4 pH-értéken, az oldódási profil magában foglal egy 7-néí kisebb vagy ezzel egyenlő óra, előnyösen egy 5-nél kisebb vagy ezzel egyenlő óra, és még előnyösebben egy 1 és 5 óra közötti időtartamú késleltető fázist; * az 1,4 pH-rőí a 7,0 pH~ra való átmenet egy olyan kibocsátási fázist eredmé-nyez, amelynek nincs holtideje: * és tartalmaz egy, legalább egy, olyan csoportokat hordozó A hidrofil polimert tartalmazó kompoz« anyagot, amelyek semleges pHm ionizálnak, vatamlnt legalább egy B hldrofőb vegyülefet; azzal jaiiamazva, begy a mikrokapszuiák közül legalább egyesek tartalmaznak legalább egy kiböilátásl segítő anyagot, arra a célra, bogy a hatóanyagCok) módosítói kibocsátására szolgáló bevonat permeabliítását növelje, és, bogy a késleltető fázis alatt kibocsátott hatóanyag(ok) tömeghányada kisebb, mint 15 tőrbéi% per óra, vagy ezzel egyenlő, előnyösen kisebb, mint 10fömeg% per őre, vágy azzélegyenlő, és még előnyösebben kisebb, mint ö tömegé per óra, vagy ezzel egyenlő. 1i. A 18, igénypont szerinti gyógyásza! termék, azzal JeSfemezya» hogy a kÉoosátást segítő anyag legalább egy duzzadást elősegítő anyagból áli, Ä A 18. vagy 18. igénypont szerinti gyógyászati termék, azzal Jellémezvái a bevonat a mikrokapszulákon egy olyan ln vitro oldódási viselkedést kölese- 71SSWS0 nüz, hogy 16 óra ÄIÄII pH-értéken a hatóanyagCok) legalább 50 tömeg %~a kibocsátásra kerülAn oral pharmaceutical product comprising a plurality of active ingredient (s) of modified modified nucleic acid, in at least some of the microcapsules, an active ingredient, in particular at least one low solubility earedilolfol differential excipient containing a microparticle, coated with at least one, the release of the active ingredient (s) with a word-capping coating, imily release controlled by two different triggering mechanisms, where one is based on a pH change, and the other is to allow the release of the predetermined residence time of the substance (s) in the stomach and said levon: * imparts an in vitro dissolution behavior to the microcapsules that: - is constant at pH 1.4, the dissolution profile includes less than or equal to 7 hours, preferably less than 5; or equal and, more preferably, a delay phase of from 1 to 5 hours; * The transition to pH 1.4 at pH 7.0 results in an emission phase with no dead time: * and contains a composite of at least one hydrophilic polymer A carrying groups that are neutral. pHm is ionized, with at least one compound of formula B; with at least some of the microcapsules containing at least one excipient for the purpose of increasing the permeability of the coating for the release of the active ingredient (s), and that the weight ratio of the active substance (s) released during the delay phase is less than 15% by weight. per hour, or less, preferably less than 10% by weight per guardian, desire is equal to, and more preferably less than or equal to, weight per hour. 1i. The healer of claim 18! product with JeSfemezya »that the excipient is comprised of at least one swelling promoter, A pharmaceutical product according to claim 18 or 18, characterized in that the coating on the microcapsules has an in vitro dissolution behavior in millet 71SSWS0 nüvi to 16 hours. The pH of the active ingredient Cok is at least 50% by weight 21. Gyógyászati lirbtik* különösen, de nem az 1-20. igénypontok egyike ste-rínti korlátozással, azzal Jellemezve, begy tartalmazza a carvediíoMól eltérd hatôanyago(ka}t ta bal mazó míkroegységek különböző populációjának keverékét, ezek a populációk pedig, in vitro oldékonyságí profiljaikban különböznek egymástól legalá!! egy, az 1,4 és 7,4 kézé eső pH-értéken. 22» A 20. igénypont és legalább egy, a többi megelőző Igénypont szerinti gyógyászati termék azzal Jellemezve, hegy a míkroegységek a hatóanyag fok) módosított kibocsátására képes mikrokapszulák és, adott esetben, a hatóanyag(ok| azonnali kibocsátáséra képes mikroegyséfsk. 26. A 21. igénypont szerinti győgyászati termék azzal jellemezve, hogy a hatóanyag módosított kibocsátására képes mikrokapszulák populációi, ezek megfeleld kiváltó pH-jukban különbőznek egymástól, 24. A 21. Igénypont szerinti gyógyászati termek azzal Jellemezve, hegy e hatóanyag módosított kibocsátáséra képes nikrokápszülák popuilóÉi ezek megfelelő kiváltó idöjeikben különböznék egymástól» 21, Á 21. igénypont szerinti gyógyáS|il termék ezzel Jellemezve, hogy tartalmaz: i azonnal kibocsátásra képéi hatóanyagot tartalmazó míkroegységek popylaeigia-ból legalább egyet; il. a hatóanyag(ok) módosított kibocsátásra képes mÉrekspszyiák P1: póppiációjá·. ból legalább egyet; és ül, a hatóanyagíok; módosított kibocsátásra képes míkr okapszülék P2 populációja-bóí legalább egyet; és, hegy a P1 és P2 megfelelő kiváltó pH-iai legalább 0,5 pH-egységben, előnyösen legalább 0,6 ρΗ-egysègben, és még előnyösebben legalább 0,9 pH-egységien kü-ionböznek egymástól. 26» A 21. Igénypont szerinti gyógyászé! termék azzal jelemeive, hogy a ha-íőanyag(ok) módosított kibocsátásra képes mikrokapszulák különböző populációinak megfelelő kiváltó pB-értékei 5 és 7 között vannak. 2Î. A 21. igénypont szerinti gyógyászati termék azzal jellemezve, hogy tartalmaz: ΐ; azonnali kibocsátásra képes hatóanyagot tartalmazó mikroegységek populádójá-bál legalább agyaik tiátóanyago|ka)t tartalmazó míkroegységek, olyan PV populációjából legalább agyat, amelyet á haffanyagofk) módosítói kiboositisira képes olyan mikrokap» míiak alkotnak, amelyekre a kiváltó pH értéke 5,5.; és m, haté3nyago(ka)t tartalmazó míkroegységik, olyan P2S populációjából legalább egyet, amelyet a haióanyago(k) módosított Elbocsátására képes olyan rnikrokap·' szülik alkotnak, arneípkre a kiváltó pH értéke 6,0 vagy 6,5 2i, A 21-2?. igénypontok egyike szerinti gyógyászati termék azzal Jellemez» va, bogy a kibocsátási profil, amelyet agy in vitro kibocsátási tesztben mérünk, az alábbiak szerint javallott: - a haióanyagt'ök} kevesebb, mint 20%~a kerül kibocsátásra 2 óra elteltével, pH~i ,4 értéken; - a hatóanyagtól} legalább 50%-a kerül kibocsátásra 16 óra elteltével, pH-1,4 értéken; II, á 21-28, igénypontok egyike szerinti gyógyászati termék ezzel Jellemez* ve* bogy tartalmaz azonnali kibocsátásra képes hatóanyagot tartalmazó mikrocgysé-§ak populációjából legalább egyet, amely egy in vitro oldódási tesztben olyan viselkedést mutat, hogy a haióanyag(ok) legalább 80%-a kerül kibocsátásra 1 óra elteltével, az 1,4 és 7,4 közötti pH-értékek bármelyikén, 8fh A 21-29. igénypontok egyike szerinti gyógyászati termék ezzel Jellemezve, begy a biféányago{ka}t tartalmazó rníkroegységekóeo az alaosony oldékony-Sági batÓanyag{olt binpdé {amely á mikroegységek teljes tômégire vonatkoztatott száraz tömeg%~ban van kifejezve) 5 és 10 közdttl; iilbyősen 10 és 70 közötti, és még előnyösebben 15 és 60 közöli, 81* A 21-30. Igénypontok egyike szerinti gyógyászati termék azzal jellemezei begy az azonnali kibocsátásra képes hatóanyagot tartalmazó mlkroegységek li. Az előzd Igénypontok egyike szerinti gyógyászati termék ezzel jellemez-*** bogy ezt egy naponta egyszeri; olyan orális dózis formájában biztosítjuk, amely ÓOög«5ogggg, a; batéádyágfól) módosított kibocsátására képes mikrokapszufál tar- ?UZ47/B021. Specially, but not limited to, pharmaceuticals. One of the claims of Claims 1 to 4, characterized in that it contains an active ingredient other than carvedicol (a mixture of the different populations of the left micron units) and these populations differ in their in vitro solubility profiles by at least one, 1.4 and 7, respectively. , 4 hands at pH 22. 22 The pharmaceutical product according to claim 20 and at least one of the preceding claims, characterized by modified microcapsules having the capability of acting as the degree of action of the microparticles and, where appropriate, the active ingredient (s) | 26. A pharmaceutical product according to claim 21, wherein the populations of microcapsules capable of delivering a modified release of the active ingredient differ at their respective pH, 24. The pharmaceutical room according to claim 21, characterized in that said drug is a modified agent. Nichocap capable of emitting Paramiloids of their parents differ in their respective triggering times »21, A medicament according to claim 21, comprising: i) at least one of the microbial units containing the active ingredient for immediate release from popylaeigia; yl. the active substance (s) can be modified to produce P1: pegylation ·. at least one of them; and sitting, the drugs; a population of at least one of the P2 populations of modified capillary capillaries; and, at a suitable pH of P1 and P2, at least 0.5 pH units, preferably at least 0.6 ρben, and more preferably at least 0.9 pH units. 26 »The healer of claim 21! product has the corresponding pB values of different populations of microcapsules capable of delivering modified release (s) to between 5 and 7. 2i. Pharmaceutical product according to claim 21, comprising:; microparticles containing at least a brain of a population of at least one brain that is capable of modifying the excitatory exponents of a microparticle containing the active substance containing immediate release active ingredient, for which the pH of the trigger is 5.5; and m, having a subunit (s) of microspheres, at least one of a population of P2S that is a parent of a modified capsid (s) capable of displacing the excipient (s), has a pH of 6.0 or 6.5 2i for arnipods, 2 ?. A pharmaceutical product according to any one of claims 1 to 4, characterized in that the release profile measured in an in vitro emission test for the brain is indicated as follows: - the substance is less than 20% is released after 2 hours, pH ~ i , 4; at least 50% of the active ingredient is released after 16 hours at pH 1.4; A pharmaceutical product according to any one of claims 21 to 28, comprising at least one of the population of microcircuits containing an active ingredient capable of immediate release, which exhibits a behavior in an in vitro dissolution test that at least 80% of the excipient (s) is present. % is released after 1 hour at any of the pH values between 1.4 and 7.4, 8fh A 21-29. A pharmaceutical product according to any one of claims 1 to 4, characterized in that it comprises a compound of the formula (s) having a soluble solubility (expressed as a percentage by weight of the total mass of microparticles) of 5 to 10 impurities; 10 to 70, and more preferably 15 to 60, 81 * to 21-30. The pharmaceutical product according to one of the claims is characterized by the inclusion of the micron units containing the active ingredient capable of immediate release. The pharmaceutical product according to one of the preceding Claims is characterized by this - *** it is once a day; in the form of an oral dosage form which is Ooh 5gggg, a; batéadyágf) modified microcapsule bullet capability UZ47 / B0 35. Az előző Igénypontok egyike szerinti gyógyászati termék éiiil jellemezve* őzt egy mikrokapsxuía-por tasskjának, mikrokapszuiák folyadék szuszpen-ziójának, mikrokapszuíákbói nyert tabletta vagy egy mikrokapszuíákat tartalmazó zselatin kapszula formájában biztosijuk, Ä Az előzd Igénypontok egyike szerinti gyógyászati termék aaset jellemezve* bogy a hatéanyago(ka}t a következő, nagy változatosságé hatóanyagok legalább egyike közi! választjuk ki: fekélyellenes szerek, aníldíabetlkus szerek, antikoaguíán-sok, antlirembotikus szerek, v^rzsír-csőkkentó szerek, antiarilmlás szerek, értág ltok, angina-ellenes szerek, arilhípertenzlv szerek, érvédő szeréi,: termékenységet elise-gitók szerek, méhtevékenységet Irtdukáié is elősegíti szerfk, fogamzásgátlók, arttl biotikumok, gombaailenes szerek, vírusellenes szerek, rákellenes szerek, gyula» déscsikkento szerek, fájdalomcsillapító szerek, anlapilepfikus szerek, Parkinsomkif eliertl szerek, leoroíepfíkimok. hipnotikus szerek, nyugtatok, pszíchostimuiánsck, migrénellenes széfék, antidipresssánsok, kohogéscsílapitók, antihisztamirtók vágy antiatiergíás szerek, szívszéihődásí angina pectoris, bal sxivkmarás Npertréfia, szív» antmiék, szívizom infarktusok, reflex tachycardia, isémlás szívbetegség, atheromatosis, diabetes me!Íftus-hoz kapcsolódó magas vérnyomás, májkapuér bipertenzló, szédülés, bradycardia, artériás alacsony vérnyomás, víz- és nátrium-retentii, akut veseelégtelenség, orthosiaiikus alacsony vérnyomás is agyinfarktus legyőzésére szolgáló szerek valamint ezek keverékei. 3&amp; Az előző Igénypontok egyike szerinti gyógyászati termék azzal jellemez» mf hegy a hatéanyago(ka}t a következő termékek által alkotott csoportból választjuk ki: acetiszalldl-sav, oarbamazepin, pentoxifyim prazosin, acyclovir, nifédipln, díitiazem, naproxen, Ibuprofen, flurbiprofen, ketoprofen, íenoproíen, índomethacín, diclofenac, fentlazao, oestradiol valerat, metoprolol, sulpirld, capfoprii, cimetidin, zidovydin, nioartlpln, terfeeadli, atenolol, salbutamol, earbamazepirt, ranitidin, enaiaprü, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, Spironolacton, 5-asa, çuinidin, perindoprll, morfin, peniazocin, paracetamol, omepmp^f, lansopri^l, métocieprirnld, amíno-szaliolsav, náildlxin-sav, amoxiolllh, amoxicillin és clavulanat kálium, amplclilln, amplcillin és sulbactam, azithromycin, baoampietlln, oerbenlclllln índanil nátrium (és más earbenicillin-sök), oapreomydn, oefadroxil, eefazolin, cephalexin, oepbaiothm, cephapirin, cophacelop cefprozi! oephadrin, cefamandol, céfonlcid, seforanid, eefyroxim, celxim, cafoperazon, 77S2ÄQ eafetaxim, cefpodoxim, ceíiaxidim, ceÄufory ceffeoxim, ceftriaxon, eefepim, eelmetazoí, oefefetan, cefoxäin: óiprbflőxáoinvW clindamycin, clofazimirp doxaciilín, cotriamoxazo!« cydoistim dscloxacilün, dirithromycin, erythromycin {és erythromycm-sók, például eétöláf*: sttagukkcinát, glucaptat, lafctobiboit* sdsaráfj, eíhamOufof~HCi és más sók, ethionamid, fosfomycín, imipenem, isonlazld, leyeflöxacm, lomefloxaoin, foraearPef, meittoiim methenamin, metronidazöl, meto&amp;lopramíd, meztodin, nafdllin, nitrofurantoin, norfloxacin, novobiocin, ofloxacin« oxsdíiin, penkdllin V, penicítNmsók, penlciilindmmpiexek, ienfarlilîl, piperadikn, pipepciHin és tazobactam, Sparfloxacin, suiphacytin, suiphameraza% sulphamethazin, suiphamefhixoi, sulphasaiazin, sulphisoxazoi, suiphapynzm, syfphadlzie, aaJpmefhoxazoi, sulphapyridin, licarciliin, ücarcüün és elavulását kà* iiam* idmáibopimplHmetrapI folaanomyein, vancornydn, verapamil és ezek keveréke, 3$. Az előző Igénypontok egyike szerinti gyógyászati termék ni ]eiepié&amp;* ve, hogy a hatóanyag(ok) az alacsony oídékonyságó hatéanyag(ok) egyike, 3?„ Az előző igénypontok bármelyikében meghatározott mikrokapszulák.A pharmaceutical product according to one of the preceding claims, characterized in that it is provided in the form of a microcapsule powder pouch, microcapsule liquid suspension, tablet obtained from microcapsules or a gelatin capsule containing microcapsules, characterized by a pharmaceutical product according to one of the preceding claims. active agent (s) selected from at least one of a wide variety of active agents: anti-ulcer agents, aniline insecticides, anticoagulants, anti-liremotic agents, liposuction agents, antiarrhythmics, vasodilators, anti-angina agents, aryl hypertensives , antiprotozoal agents: fertility enhancers, uterine activity is also promoted by dermatologists, contraceptives, arthl biotics, fungicides, antiviral agents, anticancer agents, antiperspirants, painkillers, analgesics, anapillepeptics, Parkinsomk anti-migraine, antipsychotics, heartburn angina pectoris, left sxivk etching, reflex tachycardia, myocardial infarction, reflex tachycardia; High blood pressure, hepatocellular diphtheria, dizziness, bradycardia, arterial hypertension, water and sodium retention, acute renal failure, orthosial low blood pressure, and mixtures thereof. 3 &amp; A pharmaceutical product according to one of the preceding Claims, characterized by a mf of the active ingredient selected from the group consisting of acetic acid dicarboxylic acid, carbamazepine, pentoxifyaz prazosin, acyclovir, nifedipln, dithiaemia, naproxen, Ibuprofen, flurbiprofen, ketoprofen, propenol. , dinomethacin, diclofenac, fentanyl, oestradiol valerate, metoprolol, sulpirld, capfopril, cimetidine, zidovydin, nioartlpln, terfehead, atenolol, salbutamol, earbamazepirt, ranitidine, enaapril, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, spironolacton, 5- asa, quinidine, perindopril, morphine, peniazocin, paracetamol, omepmp ^ f, lansopril, metocieprirnld, aminosalic acid, sodium lxinic acid, amoxiolllh, amoxicillin and clavulan potassium, amplclilln, amplcillin and sulbactam, azithromycin, baoampietin, oerbenlclinyldanil sodium (and other earbenicillins), oapreomydn, oefadroxil, eefazolin, cephalexin, oepbaiothm, cephapirin, cop hacelop cefprozi oephadrin, cefamandole, céfonlcid, seforanid, eefyroxim, celxim, cafoperazon, 77S2ÄQ eafetaxim, cefpodoxime, ceíiaxidim, ceÄufory ceffeoxim, ceftriaxone, eefepim, eelmetazoí, oefefetan, cefoxäin:! óiprbflőxáoinvW clindamycin, clofazimirp doxaciilín, cotriamoxazo "cydoistim dscloxacilün, dirithromycin , erythromycin {and erythromycm salts, such as ethanol *: sttaguccinate, glucaptat, lafctobiboit * sdsar, yofofo-HCl, and other salts, ethionamide, fosfomycin, imipenem, isonlazld, leyefloxacm, lomefloxaoin, foraearPef, girls methenamine, metronidazole, meto &amp; meztodin, nafdllin, nitrofurantoin, norfloxacin, novobiocin, ofloxacin «oxsdíiin, penkdllin V penicítNmsók, penlciilindmmpiexek, ienfarlilîl, piperadikn, pipepciHin and tazobactam, sparfloxacin, suiphacytin, suiphameraza% sulphamethazin, suiphamefhixoi, sulphasaiazin, sulphisoxazoi, suiphapynzm, syfphadlzie, aaJpmefhoxazoi, sulphapyridin , licarcilin, ücarcün and obsolescence over * iiam * idmáibopimplHmetrapI folaanomyein, vancornydn, verapamil and a mixture thereof, $ 3. The pharmaceutical product according to one of the preceding claims, is that the active ingredient (s) is one of the low solubility (s), (3) microcapsules as defined in any one of the preceding claims.